Conditions: HER-2 Positive Breast Cancer Metastatic Neoplasm
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 624
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether patients with metastatic breast cancer treated with margetuximab plus chemotherapy have longer progression free survival (PFS) and overall survival (OS) than patients treated with trastuzumab plus chemotherapy.

A non-randomized sub-study cohort of approximately 88 patients will be enrolled to evaluate the safety of a reduced margetuximab infusion rate in patients receiving margetuximab either as monotherapy or in combination with chemotherapy.

Detailed description:

Arms:
arm 1: Margetuximab 15 mg/kg every 21 days arm 2: Trastuzumab 8 mg/kg loading dose, then 6 mg/kg every 21 days arm 3: Margetuximab 15 mg/kg every 21 days (with or without chemotherapy), studying a shorter duration of infusion beginning in Cycle 2.

Interventions: intervention 1: Margetuximab intervention 2: Trastuzumab intervention 3: Physician's choice of chemotherapy.
Intervention descriptions: intervention 1: 15 mg/kg via IV (intravenous) infusion on day 1 of each 21 day cycle, intervention 2: 8 mg/kg via IV (intravenous) infusion for the first dose and 6 mg/kg for all subsequent doses via IV infusion on day 1 of each 21 day cycle intervention 3: Capecitabine (Xeloda®):1000 mg/m2 BID for 14 days in a 21-day cycle, or Eribulin (Halaven®): 1.4 mg/m2 on days 1 and 8 of a 21-day cycle, or Gemcitabine (Gemzar®): 1000 mg/m2 on days 1 and 8 of a 21-day cycle, or Vinorelbine (Navelbine®): 25-30 mg/m2 on days 1 and 8 of a 21-day cycle

Protocol document:
Prot_000.pdf: 
Margetuximab
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020
CLINICAL TRIAL PROTOCOL: CP-MGAH22-04
PROTOCOL AMENDMENT 4 
Study Title:
A Phase 3, Randomized Study of Margetuximab Plus 
Chemotherapy vs Trastuzumab Plus Chemotherapy in the 
Treatment of Patients with HER2+ Metastatic Breast 
Cancer Who Have Received Prior Anti-HER2 Therapies 
and Require Systemic Treatment
Study Number:
CP-MGAH22-04
Study Phase:
3  
Product Name:
Margetuximab
IND Number:
EudraCT Number: 
2015-000380-13
Indication:
Metastatic or Locally Advanced HER2-positive Breast 
Cancer
Coordinating Principal 
Investigator:
TBD
Sponsor:
MacroGenics, Inc.
9704 Medical Center Drive
Rockville, MD 20850
USA
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. 
Confidential
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NCT02492711 


Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
 
 
 
Confidential
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Margetuximab
MacroGenics, Inc.
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020
Confidential
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
Confidential
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LIST OF TABLES  
 
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LIST OF FIGURES  
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LIST OF APPENDICES  
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 3, Randomized Study of Margetuximab Plus Chemotherapy vs. 
Trastuzumab Plus Chemotherapy in the Treatment of Patients with HER2+ 
Metastatic Breast Cancer Who Have Received Prior Anti-HER2 Therapies and 
Require Systemic Treatment 
Study Number: 
CP-MGAH22-04 
 
 
 
 
 
This clinical study protocol has been approved by the Sponsor:  
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Vice-President, Clinical Research 
MacroGenics, Inc. 
 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Senior Director, Biostatistics 
MacroGenics, Inc. 
 
 
 
 
 
 
Confidential
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
21CFR 
United States Code of Federal Regulations, Title 21 
β-hCG 
Beta human chorionic gonadotropin 
ADA 
Anti-drug antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the concentration-time curve 
BID 
Twice daily 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
Cmax 
Maximum serum concentration 
Ctrough 
Trough serum concentration 
Ca 
Calcium 
CAP 
College of American Pathologists 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CDR 
Complementarity-determining region 
Ch4D5 
Chimeric 4D5 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
CHF 
Congestive heart failure 
Cl 
Chloride 
CI 
Confidence interval 
CL 
Plasma clearance 
CR 
Complete response 
CRO 
Contract research organization 
CRS 
Cytokine release syndrome 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DBP 
Diastolic blood pressure 
DoR 
Duration of Response 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
E-R 
Exposure-response 
ER 
Estrogen receptor 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FcγR 
Fc gamma receptor 
FISH 
Fluorescence in situ hybridization 
FFPE 
Formalin-fixed paraffin embedded 
GCP 
Good Clinical Practice 
HC 
Heavy chain 
hCG 
Human chorionic gonadotropin 
Hct 
Hematocrit 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
HEENT 
Head, eyes, ears, nose, and throat 
HER2+ 
Human epithelial growth factor receptor 2 positive 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQoL 
Health-related quality of life 
HR 
Hazard ratio 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IL 
Interleukin 
Ig 
Immunoglobulin  
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IRE 
Immediately Reportable Event 
ISH 
In-situ hybridization  
IUD 
Intrauterine device 
IV 
Intravenous 
IxRS 
Interactive Response System 
K 
Potassium 
Kg 
Kilogram 
LC 
Light chain 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricle ejection fraction 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
mm 
Millimeter 
msec 
Millisecond 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition scan 
Na 
Sodium 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NFBSI-16 
Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom 
Index - 16 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PE 
Physical examination 
PES 
Polyethersulfone 
PFS 
Progression free survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPK 
Population pharmacokinetics 
PO 
By oral administration 
PR 
Partial response 
PgR 
Progesterone receptor 
PRO 
Patient reported outcome 
PT 
Prothrombin time 
PVC 
Polyvinyl chloride 
Q3W 
Every 3 weeks 
QW 
Every week 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
RANKL 
Receptor activator of nuclear factor kappa B ligand 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Stable disease 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
Thalf 
Terminal half-life 
Tmax 
Time to maximum serum concentration 
T-DM1 
Ado-trastuzumab emtansine 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
IND Number: 
 
Name of Finished Product: Margetuximab 
Study Title: 
A Phase 3, Randomized Study of Margetuximab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy in 
the Treatment of Patients with HER2+ Metastatic Breast Cancer Who Have Received Prior Anti-HER2 
Therapies and Require Systemic Treatment 
Study Number: 
CP-MGAH22-04 
Investigator(s)/Centers:  
This study will be executed at approximately 200 centers in approximately 25 countries. 
Study Phase: 3 
Primary Objectives 
The primary objective of this study is to evaluate the efficacy, as measured by progression-free survival (PFS) 
assessed by independent review and overall survival (OS), of margetuximab plus chemotherapy compared 
with trastuzumab plus chemotherapy in patients with advanced HER2+ breast cancer who have received at 
least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having received 
(neo)adjuvant pertuzumab, at least 1 prior line of  anti-HER2 directed therapy in the metastatic setting, and 
who have received at least one, and no more than three, lines of therapy overall in the metastatic setting.  
Infusion Sub-Study: The primary objective of the infusion sub-study is to determine the safety and 
tolerability of margetuximab administered at a reduced infusion time in Cycle 2 and beyond. The incidence of 
Grade 3 or greater infusion-related reactions (IRRs) by the end of Cycle 2 is the outcome measure.  
Secondary Objectives 
• 
To evaluate PFS, as assessed by study investigators, of margetuximab plus chemotherapy vs. trastuzumab 
plus chemotherapy in these patients. 
• 
To evaluate by independent review, the objective response rate (ORR) of margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
Infusion Sub-Study: To evaluate the incidence of all Grade infusion-related reactions in all sub-study 
patients. 
Tertiary Objectives 
• 
To evaluate health-related quality of life (HRQoL), as assessed using the Network-Functional 
Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI) -16 and EQ-5D-5L, associated 
with margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
• 
To characterize the safety profile of margetuximab plus chemotherapy vs. trastuzumab plus 
chemotherapy in these patients. 
• 
To evaluate the clinical benefit rate (CBR) of margetuximab plus chemotherapy vs. trastuzumab plus 
chemotherapy in these patients.  
• 
To evaluate ORR, as assessed by study investigators, of margetuximab plus chemotherapy vs. 
trastuzumab plus chemotherapy in these patients. 
• 
To evaluate the duration of response (DoR) of margetuximab plus chemotherapy vs. trastuzumab plus 
chemotherapy in these patients.  
• 
To characterize the population pharmacokinetics (PPK) and exposure-response (E-R) relationships of 
margetuximab in these patients. 
• 
To evaluate anti-drug antibodies (ADA) directed against margetuximab and its effects on 
pharmacokinetics (PK), efficacy, and safety in these patients. 
 
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Margetuximab 
MacroGenics, Inc. 
Clinical Trial Protocol: CP-MGAH22-04 
Amendment 4, 08 June 2020 
 
 
Exploratory Objective 
To evaluate the effect of allelic variation in CD16A, CD32A, and CD32B on the efficacy of margetuximab in 
all patients receiving study treatment. 
Rationale 
Therapy directed against HER2, either via a monoclonal antibody or derivatives or by small molecule 
inhibition, has shown efficacy in patients with advanced breast cancer. To date, no HER2-targeted agents 
have been approved in the United States (US) to specifically treat patients after two prior lines of treatment, 
although both lapatinib and trastuzumab are often used in this setting. The purpose of this study is to evaluate 
the activity of margetuximab in combination with standard of care chemotherapies in the setting of patients 
with metastatic HER2+ breast cancer who have received at least 2 prior lines of anti-HER2 directed therapy in 
the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-
HER2 directed therapy in the metastatic setting, and who have received at least one, and no more than three, 
lines of therapy overall in the metastatic setting. Because common practice is to treat these patients with an 
anti-HER2 agent in combination with chemotherapy, it is unethical to compare the effect of margetuximab 
with placebo, and therefore an active comparator was chosen. Trastuzumab is commonly used in this setting, 
and the comparison will directly evaluate whether enhanced antibody dependent cell-mediated cytotoxicity 
(ADCC) produces superior clinical efficacy. Although not approved in this setting, trastuzumab is an 
acceptable comparator because continued treatment with trastuzumab after failure while on trastuzumab has 
demonstrated clinical benefit. In addition, trastuzumab has a generally favorable toxicity profile compared 
with lapatinib, and is commonly used in clinical practice (4, 15). 
The decision to allow physician’s choice of chemotherapy from among a selected list is based on the 
well-described finding (7) that, in the treatment of advanced breast cancer, sequential single agent 
chemotherapies are superior to combination therapy, and that, other than eribulin – which showed a modest 
survival benefit - no one agent has been clearly shown to be superior to another in the salvage setting. 
Common practice is to choose a therapy based on individual patient needs and combine that with trastuzumab. 
Rather than dictate the therapy, investigators will choose the patient’s combination chemotherapy from a 
predetermined list, allowing for a tailored approach to each individual patient’s status (also similar to the 
control arm in the eribulin pivotal study (6). To minimize bias, the selected chemotherapy will be chosen and 
documented prior to patient randomization. 
Infusion Sub-Study: This protocol will include a sub-study that reduces infusion time from 120 to 
30 minutes. Reduced infusion times will decrease the burden on patients receiving margetuximab.   
Study Design 
Overview 
This is a Phase 3, randomized, open-label, comparator-controlled study comparing margetuximab to 
trastuzumab, each in combination with chemotherapy, for the treatment of patients with advanced HER2+ 
breast cancer who have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, 
or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in 
the metastatic setting, and who have received at least one, and no more than three, lines of therapy overall in 
the metastatic setting. Patients must have progressed on or following the most recent therapy. Eligible patients 
will be assigned to chemotherapy of the investigator’s choice to be chosen from capecitabine, eribulin, 
gemcitabine, or vinorelbine. The selected chemotherapy must be allowed for use per local regulations. Upon 
meeting all entry criteria, patients enrolled in the study will be randomized 1:1 to receive either margetuximab 
or trastuzumab to be administered in combination with the chosen chemotherapy. Patients will be treated until 
disease progression, death, withdrawal of consent, or request by the treating physician to discontinue 
treatment. Following completion of (or discontinuation from) treatment, patients will be followed for survival. 
The study will include a non-randomized sub-study cohort of approximately 78 subjects with HER2+ 
metastatic breast cancer to receive either single agent margetuximab or margetuximab in combination with the 
Investigator's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). This infusion sub-
study will enroll patients meeting all criteria for the randomized study with the exception of the requirements 
for prior therapy; the infusion sub-study will require patients to have received at least 4 prior lines of therapy 
for metastatic breast cancer, as well as prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-
DM1).   
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Treatment Groups 
Patients in the randomized portion of the study, will receive either margetuximab or trastuzumab in 
combination with the preselected chemotherapy of the investigator’s choice. Patient randomization will be 
stratified by number of metastatic sites (≤2, >2), number of lines of therapy in the metastatic setting (≤2, >2), 
and choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). 
Patients in the Infusion Sub-Study will receive margetuximab alone or in combination with protocol-specified 
physician choice chemotherapy.  
Study Population 
This study will enroll patients with advanced HER2+ breast cancer who have received at least 2 prior lines of 
anti-HER2 directed therapy in the metastatic setting, or in case of having received (neo)adjuvant pertuzumab, 
at least 1 prior line of anti-HER2 directed therapy in the metastatic setting, and who have received at least 
one, and no more than three, lines of therapy overall in the metastatic setting.  
The infusion sub-study will enroll a similar patient population with the exception of requiring at least 4 prior 
lines of therapy (including trastuzumab, pertuzumab and T-DM1) for metastatic HER2+ breast cancer, so that 
there is no direct overlap with the primary study population for the randomized component of this trial. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
To be included in this study, patients must: 
General 
1. Be able 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 and completion of HRQoL assessments.  
2. Be ≥ 18 years old. Patients may be male or female. 
3. Have histologically proven, metastatic or locally advanced, relapsed/refractory HER2+ (3+ by IHC or 
ISH-amplified as per American Society of Clinical Oncology [ASCO] and the College of American 
Pathologists [CAP] Guidelines) breast cancer based on the most recently available tumor biopsy collected 
from the patient. HER2 status must be documented from a reference laboratory that conforms to standards 
set for accreditation by CAP or an equivalent accreditation authority. Confirmatory IHC testing is not 
required for study entry. Tumors may be estrogen receptor (ER)/progesterone receptor (PgR) positive or 
negative. 
4. Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of 
having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the 
metastatic setting. In either case, patients must have received prior treatment with pertuzumab in the 
(neo)adjuvant or metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 
therapies are allowed.  
5. Have received treatment with at least one, and no more than three, lines of therapy overall in the 
metastatic setting. Hormonal therapies will not be considered when determining the number of previous 
lines of therapy in the metastatic setting. Prior neo-adjuvant or adjuvant therapy that resulted in relapse 
within 6 months of the completion of therapy will be considered a line of treatment for metastatic disease. 
Eligible patients must have progressed on or following, the most recent line of therapy. Dose 
interruptions, delays, pauses during previous therapy, or changes in therapy to manage toxicity will not 
constitute a new line of therapy provided disease progression did not occur.  
6. Resolution of all chemotherapy or radiation-related toxicities to ≤ Grade 1 (with exception of ≤ Grade 2 
alopecia, stable sensory neuropathy, or stable electrolyte disturbances that are managed by 
supplementation). 
7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 4). 
8. Have life expectancy ≥ 12 weeks. 
9. Have either measurable or non-measurable disease as per RECIST 1.1 criteria and documented by CT 
and/or MRI. 
Laboratory Features 
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10. Have acceptable laboratory parameters as follows:  
a. Platelet count ≥ 100 × 103/µL without having received a transfusion or growth factor support within 
4 weeks prior to randomization. 
b. Hemoglobin ≥ 9.0 g/dL without having received a transfusion or growth factor support within 4 weeks 
prior to randomization. 
c. Absolute neutrophil count ≥ 1.5 × 103/µL in the absence of any growth factor support given within 
4 weeks prior to randomization. 
d. Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) ≤ 3.0 × the upper limit of normal 
(ULN), except patients with liver metastases, who may enroll with ALT/AST ≤ 5.0 × ULN. 
e. Total bilirubin ≤ 1.5 × ULN, except patients with Gilbert’s syndrome, who may enroll if the 
conjugated bilirubin is within laboratory normal limits. 
f. Creatinine < 1.5 mg/dL, or a calculated or measured creatinine clearance > 50 mL/min. 
Reproductive Features 
11.  Female patients of childbearing potential (not surgically sterilized and between menarche and 1 year post 
menopause) must have a negative result from a serum pregnancy test performed within 14 days of 
randomization and a negative serum or urine pregnancy test on the day of first study treatment prior to the 
initiation of study treatment.  
   
 
Further, female patients of childbearing potential must agree to use highly effective contraceptive 
measures from the time of informed consent through 7 months after the last dose of study drug (either 
margetuximab or trastuzumab). Highly effective methods of contraception include:  
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with the 
inhibition of ovulation 
o 
Oral  
o 
Intravaginal 
o 
Transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
o 
Oral  
o 
Injectable 
o 
Implantable 
o 
Intrauterine device (IUD) 
o 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence 
 
12. Male patients should also have their partners who are women of childbearing potential use a highly 
effective method of contraception (as shown above) from the time of informed consent through 7 months 
after last dose of study drug (either margetuximab or trastuzumab). 
 
Exclusion Criteria:  
Patients who meet any of the following criteria will be excluded from the study: 
1. Patients with known, untreated brain metastasis.  
• 
Patients with signs or symptoms of brain metastasis must have a CT or MRI performed within 4 
weeks prior to randomization to specifically exclude the presence of radiographically detectable 
brain metastases.  
• 
Patients with known, treated brain metastases must have a baseline CT or MRI within 4 weeks of 
randomization and are eligible provided all therapy for the metastases concluded at least 4 weeks 
prior to randomization, or, if continued steroid therapy is indicated following therapy, they have been 
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on a stable dose of steroids (≤ 10 mg/day of prednisone or equivalent) for at least 4 weeks prior to 
randomization with no symptoms.  
2. History of uncontrolled seizures within 6 months of randomization. 
3. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation.  
4. Treatment with any local or systemic anti-neoplastic therapy (including hormonal therapies for breast 
cancer) or any investigational therapy within 2 weeks prior to randomization. Bisphosphonates and 
receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors are allowed provided treatment 
starts prior to randomization. 
5. Treatment with corticosteroids (i.e., > 10 mg prednisone per day or equivalent) or other immune 
suppressive drugs within 2 weeks prior to randomization. Steroids for topical use, inhalational use, nasal 
spray, or ophthalmic solution are allowed. 
6. History of clinically significant cardiovascular disease including but not limited to: 
a. 
Myocardial infarction or unstable angina within 6 months prior to randomization.  
b. Stroke or transient ischemic attack within 6 months prior to randomization. 
c. 
Clinically significant cardiac arrhythmias. 
d. Uncontrolled (persistent) hypertension defined as systolic blood pressure (SBP) >180 mmHg or 
diastolic blood pressure (DBP) >100 mmHg. 
e. 
Congestive heart failure (New York Heart Association [NYHA] class II-IV). 
f. 
Pericarditis or clinically significant pericardial effusion. 
g. Myocarditis. 
h. Left ventricle ejection fraction (LVEF) < 50% by echocardiogram or multi-gated acquisition 
(MUGA) scan. 
7. Clinically significant pulmonary compromise, including a requirement for supplemental oxygen use to 
maintain adequate oxygenation. 
8. Evidence of active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 
7 days prior to randomization.  
9. Known positive testing for human immunodeficiency virus or acquired immune deficiency syndrome. 
10. Active hepatitis B or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis 
B core antigen, or hepatitis C polymerase chain reaction (PCR).  
11. Second primary malignancy that has not been in remission for at least 2 years from the anticipated start of 
study treatment. Exceptions of treated malignancies that do not require a 2-year remission include: non-
melanoma skin cancer; cervical carcinoma in situ; squamous intraepithelial lesion; localized prostate 
cancer (Gleason score < 6); resected melanoma in situ or ductal carcinoma in situ. Patients with second 
primary breast cancers within 2 years are eligible provided that both primary tumors were HER2+ (3+ by 
IHC or ISH amplified). 
12. History of trauma or major surgery within 4 weeks prior to randomization. 
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 investigational site. 
14. Known hypersensitivity to recombinant proteins, polysorbate 80, benzyl alcohol, or any excipient 
contained in the drug formulation for margetuximab, trastuzumab or other study treatments. Previous 
infusion reactions to trastuzumab or other monoclonal antibodies will not preclude enrollment provided 
no contraindication to trastuzumab therapy remains. 
15. Any condition that would be a contraindication to receiving trastuzumab as described in the approved 
local label or a condition that would prevent treatment with the physician’s choice of chemotherapy. 
16. Vaccination with any live virus vaccine within 4 weeks prior to randomization. Inactivated annual 
influenza vaccination is allowed at any time. 
17. Dementia or altered mental status that would preclude understanding and rendering of informed consent. 
18. Active or history of alcohol or other substance abuse within 1 year prior to randomization. 
19. Pregnant or breast feeding. 
20. Prior participation in a margetuximab clinical study. 
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21. Any investigative site personnel directly affiliated with this study. 
22. Employees of MacroGenics, Inc. 
23. Prisoners or other individuals who are involuntarily detained.  
24. Any issue or condition that in the opinion of the investigator would contraindicate the patient’s 
participation in the study or confound the results of the study. 
Entry Criteria for the Infusion Sub-Study: 
1. Patients will meet all entry criteria for the randomized portion of the study with the exception of inclusion 
criteria #4 and #5.  
2. Patients must have received at least 4 prior lines of therapy for metastatic disease. Hormonal therapies 
will not be considered when determining the number of previous lines of therapy in the metastatic setting. 
Prior neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of the completion of 
therapy will be considered a line of treatment for metastatic disease. Eligible patients must have 
progressed on or following the most recent line of therapy. Dose interruptions, delays, pauses during 
previous therapy, or changes in therapy to manage toxicity will not constitute a new line of therapy 
provided disease progression did not occur. 
3. Patients must have received prior trastuzumab, pertuzumab, and T-DM1. 
Study Drugs, Dose, and Mode of Administration 
Prior to randomization, investigators will choose one of four systemic chemotherapies commonly used in the 
salvage setting for advanced breast cancer (capecitabine, eribulin, gemcitabine, or vinorelbine) to be 
administered in combination with the study drug (margetuximab or trastuzumab). The chemotherapy selected 
must be allowed for use per local regulations (see Section 6.1.2 for additional information). Chemotherapy 
will be started on Day 1 of each cycle and administered according to best practices and the starting dose, 
schedule, and mode of administration described in the following table. Chemotherapy may be discontinued, 
and antibody therapy continued, after 6 cycles if patients have a response of stable disease or better. 
Study treatments (study drugs and chemotherapies) to be administered during this study are summarized in the 
following table. 
 
Agent 
Starting Dose 
Schedule 
Mode of 
Administration 
Chemotherapya 
 
 
 
    Capecitabine 
1000 mg/m2 BID 
BID for 14 days in a 21-day cycle 
Oral 
    Eribulinb 
1.4 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
    Gemcitabine 
1000 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
    Vinorelbine 
25-30 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
Study Drugs 
 
 
 
    Trastuzumab 
8 mg/kg loading dose then 
6 mg/kg 
Every 21 days 
IV 
    Margetuximab 
15 mg/kg 
Every 21 days 
IV 
BID = twice daily; IV = intravenous 
a. 
The chemotherapy selected must be allowed for use per local regulations (see Section 6.1.2). 
Chemotherapies must be used at the protocol-indicated starting doses, schedule, and route of 
administration, however dose adjustments to improve tolerability and manage toxicities are 
permitted.  
b. Dose of eribulin noted here is based on use as eribulin mesylate; if free base eribulin is used, 
equivalent dose of 1.23 mg/m2 is permitted.  
Doses may be modified as recommended in the appropriate local labels and as described in Section 6. 
 
 
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Duration of Treatment and Study Duration 
Patients will be treated with margetuximab or trastuzumab, both in combination with chemotherapy, in 
3-week (21-day) cycles. Patients will be evaluated every 2 cycles (at 6-week intervals) for radiologic and 
clinical disease progression using RECIST 1.1. Treatment decisions will be made locally based on 
investigator interpretation of available studies, but central review assessments of radiologic scans will be used 
for the primary endpoint of PFS. Study treatment will continue until evidence of disease progression, 
unacceptable toxicity, withdrawal of consent, physician recommendation to discontinue therapy, or death. The 
anticipated median PFS for the trastuzumab arm is approximately 4 months. The anticipated median PFS for 
the margetuximab arm is approximately 6 months. There is no requirement to discontinue treatment after a 
prescribed number of cycles. There is no crossover in this study. 
Approximately 530 patients, randomized 1:1 to margetuximab or trastuzumab, will be enrolled in this study. 
Following discontinuation of study treatment, patients will be followed for survival. The study will continue 
until there have been approximately 385 survival events, at which point the final survival analysis will take 
place. It is anticipated that accrual will take 24 months and that total follow up will take an additional 
16 months, for a total study duration of approximately 40 months.  
Infusion Sub-Study 
About 9 patients will receive a 120-minute margetuximab infusion in Cycle 1, in order to have 6 patients 
receive a 60-minute infusion in Cycle 2 and beyond (Stage A1). Any extra patients beyond 6 in run-in groups 
A1 or A2 will continue 120-minute infusions until the Stage B regimen is confirmed. If no stopping rules are 
met, an additional cohort of about 9 patients will be enrolled to receive a 120-minute margetuximab infusion 
in Cycle 1, in order to have 6 patients receive a 30-minute infusion at Cycle 2 and beyond (Stage A2). Patients 
enrolled into Stage A1 and A2 will be assigned to receive the reduced infusions until 6 patients have received 
reduced infusion times. In the absence of Grade 3 or higher IRRs, patients in Stage A may reduce infusion 
duration to the Stage B regimen. 
Safety events observed in Stage A will be used to inform infusion reduction schemes for a subsequent group 
of about 60 patients enrolled to Stage B, who will receive margetuximab over a 120-minute infusion in Cycle 
1, followed by either a 60-minute or 30-minute infusion in Cycles 2 and beyond. In the absence of Grade 3 or 
higher IRRs, ongoing patients in Stage A may reduce infusion duration once the Stage B duration is 
determined.  
Post-progression margetuximab may be considered on a case-by-case basis within the infusion substudy only, 
with agreement of the Sponsor.  
Details of the study design and stopping rules can be found in Section 6.7.1. 
Treatment Schedule (Procedure) 
See Schedule of Events (Appendix 1) 
Criteria for Evaluation 
Safety Assessments 
• 
Safety assessment will be based on the evaluation of AEs from the time of initiation of any study therapy 
through the End of Treatment visit (or 28 days after the last dose of study drug, whichever occurs later) 
and will be determined based on signs, symptoms, physical examination findings and/or laboratory test 
results from enrolled patients as appropriate. 
• 
All AEs (related to the protocol or not) will be collected from the time the patient receives the first dose 
of any study medication. 
• 
AEs reported between the time the patient signed the informed consent and the administration of the first 
dose of any study medication will be captured as concurrent medical history unless due to a protocol-
related procedure. 
• 
AE and SAE recording will continue until the End of Treatment visit is performed (or 28 days after the 
last dose of study drug, whichever is later). 
• 
SAEs considered related to study drug may be reported at any time, even after the patient’s final visit. 
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• 
Progression of the underlying neoplasm resulting in hospitalization or death (e.g., patient hospitalized for, 
or dies from disease progression only, without any other SAE) will be documented as an anti-tumor 
activity outcome and not as an SAE. If an SAE occurs in a patient and it is unclear whether the event is 
related to progressive disease, the SAE should be reported. 
Efficacy Assessments 
Tumor assessments will be obtained at Screening using CT and/or MRI scans at time intervals as specified in 
Appendix 1 (Schedule of Events). Assessment of skin lesions may be made by photography with a reference 
ruler or by caliper measurement as described in RECIST 1.1. Treatment will continue until disease 
progression, withdrawal from the study, or death. At each on-treatment tumor assessment time point, 
radiologic assessment of tumor status will be made using RECIST 1.1 criteria. Investigators will assess tumor 
response(s) for determination of suitability for continued therapy and the secondary endpoint of Investigator-
Assessed PFS. All patients who have complete response (CR), partial response (PR), stable disease (SD), or 
non-evaluable as their local radiological assessment are eligible for further therapy. Non-radiological evidence 
of disease progression should be clearly documented in the electronic case report form (eCRF). With Protocol 
Amendment 4, central review of radiographic images is discontinued, but investigator-assessed PFS and ORR 
will continue to be measured.    
All patients will have a bone scan performed at baseline and then as clinically indicated during the study for 
the assessment of bone metastasis. Patients with a history of treated brain metastasis who are otherwise 
eligible must have a baseline brain CT or MRI within 4 weeks prior to randomization. 
When applicable, digital images of skin lesions will be obtained on the same schedule for radiographic 
evaluations.  
Patients who are discontinued from study treatment in the absence of progression will be followed up every 
3 months for tumor evaluations. Upon disease progression, all patients will be followed up every 3 months for 
survival status until death, withdrawal of informed consent, lost to follow up, or the end of study 
Pharmacokinetic Assessments 
With Protocol Amendment 4, PK sample collection will be discontinued for patients who are still receiving 
study treatment.  
Immunogenicity Assessments 
With Protocol Amendment 4, collection of samples for anti-drug antibody (ADA) assay will be decreased in 
frequency from once every 6 weeks (every 2 treatment cycles) to once every 12 weeks (every 4 treatment 
cycles), consistent with radiographic evaluation. ADA samples will continue to be collected at end of 
treatment and during follow-up.  
The generation of ADA directed against margetuximab will be assayed using ELISA. Samples positive for 
ADA will be evaluated for neutralizing activity.  
Analysis Populations: 
Three analysis populations are defined: 
• 
Intent-to-Treat Population – all patients randomized. Patients will be analyzed according to the 
treatment (margetuximab or trastuzumab) assigned during randomization. This population will be used to 
summarize baseline data and evaluate PFS, OS, and HRQoL. 
• 
Response Evaluable Population – all patients who are randomized who have measurable disease at 
baseline. This population will be used to evaluate ORR and CBR.  
• 
Safety Population – all patients who are randomized and receive any amount of any study treatment. 
Patients will be analyzed according to the actual treatment received rather than the treatment group to 
which they were randomized. This population will be used for safety, PK, pharmacodynamics (PD), and 
immunogenicity analyses. 
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Statistical Methods: 
Sample Size Determination 
There are 2 primary endpoints in this study. The first primary endpoint is centrally determined PFS and the 
second primary endpoint is OS. These two endpoints will be assessed in a hierarchical manner with PFS being 
assessed first. OS will only be assessed if a statistically significant difference is obtained in PFS. 
It is estimated that the median PFS for patients treated with trastuzumab and chemotherapy is 4 months. To 
detect a 2-month improvement in median PFS from 4 months to 6 months (HR=0.67) in patients treated with 
margetuximab plus chemotherapy, a total of 257 PFS events are required to provide 90% power at a 2-sided 
alpha=0.05. The analysis of the primary PFS endpoint will occur when about 257 events have occurred or 
when all patients have been randomized, whichever occurs later. 
The sample size is calculated to ensure 80% power for the analysis of OS. The median OS for patients treated 
with trastuzumab plus chemotherapy is estimated to be 12 months. This study is designed to detect an increase 
to a median OS of 16 months in patients treated with margetuximab plus chemotherapy (hazard ratio 
[HR]=0.75). To detect a 4-month improvement in OS from 12 months to 16 months, a total of 385 events are 
required to provide 80% power at a 2-sided alpha=0.05. It is anticipated that about 530 patients will be 
accrued to achieve this number of events. Patients will be enrolled over 24 months, and estimated to remain 
on study for an average of 16 months, for a total anticipated study duration of approximately 40 months.  
The sample size of approximately 78 patients is planned for the infusion sub-study, consisting of 18 patients 
for Stage A and about 60 patients for Stage B. The sample size of 60 patients for Stage B of the infusion sub-
study is derived to provide adequate assessment of the primary safety endpoint. 
Efficacy Analyses 
Definition of Efficacy Endpoints 
Progression-free survival – defined as the time from randomization date to the date of first documented 
disease progression or death from any cause, whichever occurs first. For patients who are not known to be 
dead or progressed at time of data cut-off for PFS analysis, the PFS will be censored at the last tumor 
assessment.    
Overall survival – defined as the time from randomization 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. 
Objective response rate – the proportion of patients in the response evaluable population achieving a best 
response of CR or PR when such responses are confirmed at least 28 days after initial observation of response. 
Patients who have baseline measurable disease but no post-baseline radiographic assessment will be 
considered as non-responders. 
Duration of response – defined as the time from initial response to date of first documented disease 
progression or death from any cause, whichever occurs first. DoR will be analyzed for responding patients 
only. For responding patients who are not known to be dead or progressed at the time of data cut-off for DoR 
analysis, the DoR will be censored at the last tumor assessment. 
Clinical benefit rate - the proportion of patients in the response evaluable population achieving a best response 
of CR, PR, or SD of duration >6 months. 
HRQoL – Patients will be administered the EQ-5D-5L and NFBSI-16 quality of life questionnaires at 
baseline, Day 1 of each odd cycle, and at study completion. Change from baseline on global scores will be 
assessed. Patients in the infusion sub-study will not complete quality of life and healthcare usage assessments. 
Analysis of Primary Efficacy Endpoints 
The primary analysis for PFS will be conducted when about 257 PFS events have occurred. Analysis of OS 
will be conducted at the time of PFS analysis and subsequently when 70% of the OS events and a final OS 
analysis when about 385 survival events have occurred.  
For both PFS and OS, Kaplan-Meier methods will be used to generate survival curves and estimate the 
median OS and PFS along with corresponding 95% confidence intervals (CIs) for each treatment group. A 
log-rank test stratified by protocol defined stratification factors will be used to compare both time-to-event 
endpoints between the two treatment groups. In addition, the hazard ratios and 95% CIs for PFS and OS will 
be assessed using stratified Cox proportional hazards models with treatment as the only covariate. 
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Analysis of Secondary Endpoints 
The secondary endpoints of investigator-assessed PFS and independent review assessed ORR will be assessed 
using the Hochberg step-up procedure for multiplicity adjustment. P-values will be assessed in descending 
order. If the least significant p-value<0.05, then both hypotheses are rejected. Otherwise, this endpoint is 
retained and the second p-value is tested at p<0.025. If a p-value<0.025 (0.05/2) is obtained, this hypothesis is 
rejected. Otherwise, both hypotheses are retained.  
Investigator-assessed PFS will be analyzed using the same methods as described above for the primary 
endpoint of PFS. 
Independent review assessed ORR will be compared between groups using a Mantel-Haenszel statistic 
stratified by protocol defined stratification factors.  
Analysis of Tertiary Endpoints 
No multiplicity adjustment will be used for tertiary endpoints. 
Duration of response, where response is assessed by study investigators and by independent review, 
respectively, will be analyzed using Kaplan-Meier methods and compared between two treatment groups 
using a stratified log-rank test. 
Investigator assessed ORR will also be compared between two treatment groups using a Mantel-Haenszel 
statistic stratified by protocol defined stratification factors. 
Clinical benefit where response is assessed by study investigators and by independent review, respectively, 
will also be compared between two treatment groups using a Mantel-Haenszel statistic stratified by protocol 
defined stratification factors. 
Change in tumor size over time will be summarized and the best percentage change from baseline will be 
presented by waterfall plots. Change calculations will be based on target lesions only. 
Direct reports from patients will be obtained using the NFBSI-16 and EQ-5D-5L Questionnaires (10, 16). 
Responses Data will be collected at baseline, Day 1 of each Odd cycle, and at the End of Treatment visit. The 
primary patient-reported outcome (PRO) endpoint for analysis will be the NFBSI-16 total score, with 
secondary analysis of the subscales that add to the total (disease related symptoms, treatment side effects, and 
function/well-being. Analyses using mixed model repeated measures using the baseline score and protocol 
defined stratification factors are planned as covariates. Subscale scores will be tabulated and summarized for 
additional analyses. Data from the EQ-5D-5L scale will be summarized by study visit. To minimize missing 
data, sites will be instructed and patients educated on the importance of recording the direct patient experience 
in order to appreciate the positive and negative aspects of treating advanced breast cancer, and they will 
specifically be trained on best practices for patient enrollment, adherence to endpoint data collection 
requirements, and methods to ensure complete data capture and management. Every effort will be made to 
collect survey data at all defined visits including at early withdrawal. Reasons for missing data will be 
summarized.  
Pharmacokinetic Analysis: Serum concentrations of margetuximab will be summarized by study visits using 
descriptive statistics and graphed over time. Any population PK modeling will be performed by an external 
vendor. An analysis plan will be created prior to analysis. 
Summary statistics will be tabulated for serum PK parameters by margetuximab dose. Geometric means and 
percent coefficients of variation will be reported for Cmax, AUCtau, AUCinf, and Ctrough; arithmetic means and 
standard deviations will be reported for Thalf, CL, and Vss; and medians, minimum, and maximum will be 
reported for Tmax. 
Exposure-Response Analyses: E-R analyses will be conducted separately using key efficacy and safety 
parameters of interest. An analysis plan will be created prior to analysis. 
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 
patients who have positive ADA at baseline that increases or decreases in titer over the course of treatment 
will be summarized. Neutralizing activity will be determined for samples with positive ADA. The effects of 
ADA on key PK, efficacy, and safety parameters will be investigated. 
Safety Analyses: AEs will be coded to the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. Only treatment-emergent AEs, as defined in Section 7.9.2, will be summarized in tables. Events 
prior to treatment (e.g., due to study-related procedure) will be listed in an appendix to the final study report.  
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Summaries of laboratory values will display descriptive statistics for numerically quantified labs. Summaries 
will be grouped by laboratory panel (e.g., hematology, blood chemistry, and urinalysis) and will be displayed 
by visit for each laboratory parameter. 
In cases where an abnormality resulted in a repeat laboratory test, the repeat value will be used for the 
summaries. A list of repeated labs including original values and repeat values will be included.  
Graphs of mean values over time may also be generated. 
Electrocardiograms (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. LVEF will be evaluated by echocardiogram or MUGA and changes from 
baseline summarized.  
Infusion Sub-Study: Summary statistics will be calculated to describe incidence of infusion-related reactions 
by grade and by cycle for margetuximab given as monotherapy or in combination with chemotherapy.  
 
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2 
BACKGROUND INFORMATION  
2.1 
HER2+ Metastatic Breast Cancer Current Therapy  
Among women, invasive adenocarcinoma of the breast is the most common non-
dermatological cancer and the second leading cause of death in the United States (US). While 
early detection and treatment have reduced the death rate associated with breast cancer, for 
women diagnosed with metastatic breast cancer (MBC) in the US, the overall prognosis 
remains poor, with an estimated 40,300 deaths due to this disease in 2014 (23). In the 
European Union (EU), mortality associated with breast cancer was estimated to affect 
92,000 individuals in 2012 (15). Metastatic breast cancer can be identified either as the initial 
presentation of the disease, or after recurrence following previous treatment for local disease. 
Prior to the era of targeted therapies, patients with HER2+ tumors had more aggressive 
tumors that foretold a shorter survival. The introduction of trastuzumab into clinical practice 
in 1998 and subsequent therapeutic developments dramatically altered the natural history of 
HER2+ MBC (14). Direct targeting of the HER2 oncoprotein lengthened survival in patients 
with HER2+ MBC to the point that now patients with HER2+ disease have a much more 
favorable prognosis than prior to the introduction of trastuzumab. 
In the US and elsewhere, several agents are approved for the treatment of HER2+ breast 
cancer. For patients who require systemic therapy as part of definitive surgical resection, 
either neo-adjuvant therapy with trastuzumab - and increasingly - pertuzumab (13), or 
adjuvant therapy with trastuzumab (21), both in combination with cytotoxic chemotherapy, is 
the treatment of choice. Treatment at the time of recurrence is determined in part by the 
length of the original treatment-free interval. Patients whose disease recurs late after adjuvant 
treatment are often treated with the same or similar anti-HER2 regimen (trastuzumab 
± pertuzumab) (2, 24)used in the neo-adjuvant or adjuvant setting. Patients whose disease 
recurs shortly after initial neoadjuvant/adjuvant therapy (within 6 months) will often proceed 
to a second-line regimen, usually ado-trastuzumab emtansine (T-DM1) monotherapy (25) or 
other anti-HER2 agents in combination with chemotherapy. The progression of therapies for 
de novo MBC is similar, with trastuzumab (± pertuzumab) used in combination with 
chemotherapy in first-line (2) and T-DM1 monotherapy or other anti-HER2 therapies in 
combination with chemotherapy used in the second-line. Of note, T-DM1 approved only for 
use in patients who have previously received trastuzumab, and the benefit of this agent as 
first-line therapy, either alone or in combination with pertuzumab, has not yet been 
demonstrated. Trastuzumab is also approved for use as a monotherapy in patients who have 
received previous chemotherapy (11), although its use is limited in this indication (14). 
Lapatinib, a small molecule tyrosine kinase inhibitor of both HER1 (EGFR) and HER2, has 
been approved in the US for use in combination with capecitabine in patients who have 
previously received an anthracycline, a taxane and trastuzumab (12) and additionally in 
Europe in combination with trastuzumab (3). In theory, this allows for lapatinib use 
immediately after T-DM1: however, in practice, lapatinib is more often used in a later line of 
therapy for patients with HER2+ tumors. Given the effectiveness of neoadjuvant, adjuvant, 
and first-line therapies in HER+ disease, more patients are surviving and suitable for later-
line therapy. However, recurrence of disease is common, and additional treatments are 
needed.  
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2.2 
Rationale for Treatment with HER2-targeting Agents After Prior 
Receipt of HER2-targeting Agents in MBC Therapy 
There is mounting evidence that continued therapy with anti-HER2 antibodies provides 
additional benefit beyond early therapy. A small study by von Minckwitz et al. (26) 
established early on that continued HER2 blockade provides benefit beyond first-line 
therapy. In this study, patients who experienced disease progression on trastuzumab and 
docetaxel were randomized to continue trastuzumab with a different chemotherapy or 
chemotherapy alone. Despite the small study population, there was a clear demonstration of 
prolonged progression free survival (PFS) among patients who continued on trastuzumab. T-
DM1 was approved based on a prolongation of PFS compared with lapatinib in patients who 
had previously received trastuzumab (25). In the recently reported trial of T-DM1 in patients 
who had previously received trastuzumab and lapatinib (17), patients who received T-DM1 
had prolonged PFS and overall survival (OS) compared with those who received physicians’ 
choice chemotherapy. Interestingly, in the physicians’ choice group, approximately 80% of 
patients received trastuzumab along with chemotherapy. Patients who demonstrated an 
objective response to trastuzumab after two prior anti-HER2 therapies in this study had a 
prolonged response with the median length of response not reached at the time of the data 
cutoff for publication. Together, these data suggest that patients who have experienced 
progression during treatment with HER2-targeted agents can still benefit from additional 
anti-HER2 therapy with the same or different agents, suggesting that the optimal treatment 
paradigm in later lines remains unsettled. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
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2.3 
Margetuximab Background  
Margetuximab (20) was derived from 4D5, the murine precursor to the humanized 
therapeutic antibody, trastuzumab. Chimeric 4D5 (ch4D5) was generated by fusing the 
mouse light chain (LC) and heavy chain (HC) complementarity-determining region (CDR) 
and framework sequences of 4D5 to a human immunoglobulin (Ig) G1 backbone. 
Margetuximab was generated from ch4D5 by removal of an N-glycosylation site in the 
LC variable region (modification of one amino acid residue) and by optimization of the 
Fc domain (modification of five amino acid residues). Margetuximab binds the HER2 
oncoprotein with affinity similar to that of trastuzumab, and preserves the direct anti-
proliferative properties of trastuzumab. The optimized Fc domain of margetuximab, however, 
confers enhanced binding to the activating low-affinity Fc receptor, CD16A. In particular, 
binding to the low-affinity allele of CD16A (CD16A-158F) is enhanced in a proportionally 
greater fashion than binding to the high-affinity allele (CD16A-158V). In addition, the 
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optimized Fc domain of margetuximab exhibits reduced binding to the inhibitory receptor, 
CD32B, a feature expected to further enhance the cell-directed cytotoxic properties of 
margetuximab. In preclinical models, margetuximab exhibits enhanced anti-tumor activity 
compared with a trastuzumab surrogate against HER2-expressing tumor cell lines in in vitro 
antibody-dependent cell-mediated cytotoxicity (ADCC) assays and in human tumor 
xenograft models in human CD16A+ transgenic mice. Since most patients carry the 
low-affinity allele of CD16A, the enhanced binding properties of margetuximab are expected 
to confer benefit to the whole patient population and not disproportionately to the high-
binding homozygous carriers (V/V genotype). Homozygous high-binding (V/V) carriers 
make up less than 20% of Caucasian, African American, and Asian populations, and the 
remainder is composed of low affinity F/F and intermediate affinity F/V carriers.  
Based on the greater activity of margetuximab compared with trastuzumab in preclinical 
animal models with low affinity CD16A+ transgenic mice, and the demonstration of 
prolonged PFS for patients with metastatic breast cancer treated with  trastuzumab in high 
affinity vs. low affinity carriers (18), it is hypothesized that margetuximab will have superior 
efficacy compared with trastuzumab when either is used to treat patients with metastatic 
breast cancer who have received two prior lines of anti-HER2 therapy.  
2.3.1 
Margetuximab Clinical Experience  
Margetuximab is being evaluated for HER2+ metastatic breast cancer in two clinical studies, 
CP-MGAH22-01 and CP-MGAH22-02. 
Study CP-MGAH22-01 is a Phase 1, open-label, single-arm, multicenter dose-escalation 
study to define the toxicity profile, maximum tolerated dose (MTD), immunogenicity, 
pharmacokinetic (PK), and potential anti-tumor activity of margetuximab in patients with 
refractory HER2+ breast cancers and patients with other carcinomas that overexpress HER2 
for whom no standard therapy is available. Two regimens of margetuximab (administered via 
intravenous [IV] infusion) are being investigated in this study: weekly dosing 
(0.1 – 6.0 mg/kg) and every 3-week dosing (10.0, 15.0, and 18.0 mg/kg). Patients with stable 
disease or evidence of disease regression are eligible for continued treatment with 
margetuximab. 
Study CP-MGAH22-02 is a single-arm, open-label, Phase 2 study of margetuximab in 
patients with relapsed or refractory breast cancer whose tumors express HER2 at a 2+ level 
by immunohistochemistry (IHC) and lack evidence of HER2 gene amplification by 
fluorescent in situ hybridization (FISH) or express HER2 at a 1+ level by IHC and have a 
value of >10.5 by HERmark® testing. The study employs a Simon-two stage optimum design 
in which an initial cohort of 21 patients will be evaluated. The original margetuximab dose 
and schedule evaluated was 6.0 mg/kg via IV infusion weekly on Days 1, 8, and 15 of a 
28-day cycle. The study protocol has been amended to evaluate margetuximab at a dose and 
schedule of 15 mg/kg via IV infusion every 3 weeks for all subsequent patients.  
To date, the safety profile of margetuximab in the Phase 1 and 2 studies is generally 
consistent with that observed for trastuzumab in the same setting. Of note, cardiac toxicity, in 
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the form of reduction in left-ventricular ejection fraction (LVEF) and/or frank congestive 
heart failure (CHF), has not been observed to date. No significant decrease (defined as an 
absolute drop of 15% or to below 50%) in LVEF has been observed in patients receiving 
margetuximab in the monotherapy studies. Several patients have received multiple cycles of 
margetuximab in these studies with no apparent cardiotoxicity. Thus, margetuximab appears 
to be well-tolerated when administered either at a dose of up to 6.0 mg/kg given every week 
for 3 weeks in a 4-week cycle schedule, or when administered up to a dose of 18.0 mg/kg via 
every 3-week dosing. 
Although not designed as an efficacy study, the Phase 1 study did demonstrate preliminary 
antitumor activity of margetuximab when used as a monotherapy in the treatment of patients 
with HER2+ tumors who had experienced multiple treatment failures with previous 
therapies. In particular, 4 of 21 patients with HER2+ MBC have experienced a partial 
response (PR) by RECIST criteria. Three of these 4 patients had received prior trastuzumab 
and lapatinib. No responses have been observed in the Phase 2 study of patients with MBC 
who express HER2 at the 2+ level by IHC or who have a HERMark® score of ≥10.5.  
Detailed clinical data for these ongoing studies are provided in the margetuximab 
Investigator’s Brochure (IB).  
2.3.2 
Margetuximab Pharmacokinetics and Dose Selection  
Clinical PK were evaluated in the Phase 1 study. A two-compartment model with parallel 
linear and Michaelis-Menten elimination adequately described the observed (interim) data. 
Model parameters were generally in agreement with those commonly expected for a 
monoclonal antibody. Single dose exposure was predicted to be approximately dose 
proportional at doses >3 mg/kg when dosed weekly for 3 weeks in 4-week cycles and 
≥15 mg/kg when dosed every 3 weeks. The terminal half-life (Thalf) was estimated at 
12.7 days. Interestingly, the individual estimates of clearance (CL) and central volume were 
slightly lower in patients with breast cancer compared with other tumor types, although the 
inter-patient variability was greater than the difference observed between groups.  
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Table 3 
Margetuximab Pharmacokinetics at Steady State – 6 mg/kg,  
15 mg/kg, 18 mg/kg – CP-MGAH22-01  
Parameter  
  (unit) 
 
Margetuximab Dose and Schedule 
6 mg/kg QWa 
N=19 
15 mg/kg Q3Wb 
N=6 
18 mg/kg Q3Wb 
N=6 
Ctrough 
  (µg/mL) 
Mean 
(SD) 
73.0  
(38.2) 
69.9  
(42.9) 
86.1  
(47.9) 
 
Median  
(95% CI) 
66.9 
(20.5 - 169) 
61 
(15.8 - 180) 
77.6 
(20.8 - 207) 
Cmax 
  (µg/mL) 
Mean 
(SD) 
217  
(58.1) 
360  
(93.9) 
429  
(103) 
 
Median  
(SD) 
211 
(125 - 355) 
345 
(222 - 590) 
417 
(263 - 660) 
AUC 
  (µg/mL*h) 
Mean  
(SD) 
84700 
(30000) 
72200 
(27200) 
87500 
(30300) 
 
Median  
(95% CI) 
80500  
(40700 - 15800) 
66800 
(35300 - 139000) 
82200 
(43600 - 160000) 
a 
Dosed once weekly (QW) for 3 weeks in 4-week (28-day) cycles 
b 
Dosed once every 3 weeks in 3-week (21-day) cycles. 
 
Steady state exposure estimates are shown in Table 3 for margetuximab when dosed at 
6.0 mg/kg weekly for 3 of every 4 weeks (n=19), 15.0 mg/kg every 3 weeks (n=6), and 
18.0 mg/kg every 3 weeks (n=6) in Study CP-MGAH22-01. At steady state, these doses and 
regimens are estimated to have very similar exposure. Serum trough concentrations (Ctrough) 
for all three doses are nearly identical, are at or above those reported for trastuzumab in 
patients with breast cancer (11), and are above that required for inhibition of HER2 signaling 
as demonstrated for trastuzumab in published reports (5). Similarly, area under the 
concentration-time curve (AUC) values are also very similar, with the 15.0 mg/kg slightly 
lower than either 6.0 mg/kg or 18.0 mg/kg. Cmax differs among the three doses, as would be 
expected with higher maximal concentrations seen in the 15.0 mg/kg and 18.0 mg/kg doses 
compared with 6 mg/kg.  
At the time of data cutoff (5 January 2015), of the 69 patients treated in ongoing studies 
CP-MGAH22-01 and CP-MGAH22-02, 48 had been treated at 6.0 mg/kg weekly for 3 of 
every 4 weeks (n=33), 15.0 mg/kg every 3 weeks (n=9), or 18.0 mg/kg every 3 weeks (n=6). 
Based on exposure data from CP-MGAH22-01, these patients can be considered as a single 
cohort of 48 patients that provides clinical experience supporting the selection of the 
15.0 mg/kg dose of margetuximab for the current Phase 3 study, despite the different mg/kg 
doses administered. 
There are no obvious differences in the safety profiles of each margetuximab dose evaluated 
to date suggesting a dose-toxicity relationship. (Details of the number and kind of adverse 
events [AEs] reported both in aggregate and by dose are available in the IB). In particular, of 
the 48 patients treated with the best studied margetuximab doses of 6.0 mg/kg, 15.0 mg/kg, 
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and 18.0 mg/kg to date, no events of congestive heart failure were recorded, and no decreases 
in LVEF of ≥ 15%, or to < 50% were observed The frequency, type, and severity of AEs 
observed in these dose groups did not differ from the overall study populations and although 
the Cmax differs for these three dose groups in a dose-related manner, no obvious difference in 
the safety profile was observed between patients treated at 6.0 mg/kg (the lowest Cmax), 15.0 
mg/kg, and 18.0 mg/kg (the highest Cmax). Given the similarity of margetuximab to 
trastuzumab, this result is to be expected as no safety differential has been reported between 
the weekly dose of trastuzumab of 2 mg/kg and the every 3-week dose of 6 mg/kg. In the 
Phase 1 study of margetuximab, 7 patients have been treated continuously with 
margetuximab for at least 26 weeks, and of these, 5 patients received doses ≥10.0 mg/kg. No 
increase in AEs was noted with prolonged exposure, and none of these patients were 
discontinued from treatment because of toxicity.  
Patients participating in the present study will be randomized to either margetuximab or 
trastuzumab, both to be administered in combination with a chemotherapy of the 
investigator’s choice to be chosen from a specified list.  
The margetuximab dose and schedule selected, 15.0 mg/kg given every 3 weeks, is based on 
the observed safety and efficacy profile of margetuximab at all doses tested to date and the 
predictable PK characteristics in the ongoing Phase 1 study. As noted, the majority of clinical 
experience with margetuximab has been gained in patients treated at 6.0 mg/kg dosed weekly 
for 3 of 4 weeks and 15.0 mg/kg and 18.0 mg/kg given every 3 weeks, all of which have 
similar exposure based on steady-state PK modeling. Similar to the findings with safety, no 
clear dose-response relationship has been observed for tumor responses between these dose 
levels, with patients demonstrating responses at multiple dose levels.  
Although both trastuzumab and margetuximab have demonstrated anti-tumor activity when 
given as monotherapy, trastuzumab has greater activity when combined with cytotoxic 
chemotherapies and is approved for such use. NCCN and European Society for Medical 
Oncology (ESMO) guidelines recommend the combination of trastuzumab with numerous 
different chemotherapy regimens, though none are preferred for the treatment of MBC 
following two prior lines of therapy (4, 19). In HER2- MBC, only eribulin has shown a very 
modest survival benefit when compared with other commonly used therapies in the 
metastatic setting (6). Trastuzumab and margetuximab share the same antigen recognition 
domain, and the preliminary safety profile of margetuximab appears similar to trastuzumab. 
Trastuzumab has been combined with capecitabine (22), eribulin (27), gemcitabine (28), and 
vinorelbine (1) in the first and later line settings. These agents in combination with 
trastuzumab have not been compared with each other in a single study in the same setting, so 
it is not possible to determine if one combination is superior to another, but all have exhibited 
acceptable safety profiles when used in combination. Because none of these chemotherapy 
agents has been shown to be superior in the later line setting, it is reasonable to allow a 
choice of any of the four chemotherapies to be used in combination with trastuzumab or 
margetuximab. The choice of chemotherapy must be allowed for use per local regulations.  
Based on the superior ADCC activity of margetuximab compared with trastuzumab in 
preclinical in vivo and in vitro models, the preclinical data demonstrating superior antitumor 
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activity associated with margetuximab, and the observation of clinical responses in patients 
who have previously received anti-HER2 therapy participating in the ongoing Phase 1 study 
(see margetuximab IB for detailed data), the combination of margetuximab plus 
chemotherapy is expected to provide enhanced efficacy and comparable safety over 
trastuzumab plus chemotherapy in patients with MBC requiring additional therapy after at 
least two previous anti-HER2 containing regimens.  
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3 
STUDY PURPOSE AND OBJECTIVES  
This is a Phase 3, randomized, open-label, comparator-controlled study of margetuximab 
plus chemotherapy versus trastuzumab plus chemotherapy in patients with advanced HER2+ 
breast cancer who have received at least 2 prior lines of anti-HER2 directed therapy in the 
metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior 
line of anti-HER2 directed therapy in the metastatic setting, and who have received at least 
one, and no more than three, lines of therapy overall in the metastatic setting.  
3.1 
Primary Objective  
The primary objective of this study is to evaluate the efficacy, as measured by progression-
free survival (PFS) assessed by independent review and overall survival (OS), of 
margetuximab plus chemotherapy compared with trastuzumab plus chemotherapy in patients 
with advanced HER2+ breast cancer who have received at least 2 prior lines of anti-HER2 
directed therapy in the metastatic setting, or in case of having received (neo)adjuvant 
pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the metastatic setting, and 
who have received at least one, and no more than three, lines of therapy overall in the 
metastatic setting.   
Infusion Sub-Study: The primary objective of the infusion sub-study is to determine the 
safety and tolerability of margetuximab administered at a reduced infusion time in Cycle 2 
and beyond. The incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end 
of Cycle 2 is the outcome measure. 
3.2 
Secondary Objective  
Secondary objectives of this study are: 
• To evaluate PFS, as assessed by study investigators, of margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
• To evaluate by independent review, the objective response rate (ORR) of 
margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in these 
patients.  
Infusion sub-study: Incidence of all Grade infusion-related reactions in all sub-study 
patients. 
3.3 
Tertiary Objectives  
Tertiary objectives are: 
• To evaluate health-related quality of life (HRQoL), as assessed using the 
Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom 
Index (NFBSI)-16 and EQ-5D-5L, associated with margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
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• To characterize the safety profile of margetuximab plus chemotherapy vs. 
trastuzumab plus chemotherapy in these patients. 
• To evaluate the clinical benefit rate (CBR) of margetuximab plus chemotherapy 
vs. trastuzumab plus chemotherapy in these patients.  
• To evaluate ORR, as assessed by study investigators, of margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
• To evaluate the duration of response (DoR) of margetuximab plus chemotherapy 
vs. trastuzumab plus chemotherapy in these patients.  
• To characterize the population PK (PPK) and exposure-response (E-R) 
relationships of margetuximab in these patients. 
• To evaluate anti-drug antibodies (ADA) directed against margetuximab and its 
effects on PK, efficacy, and safety in these patients. 
 
3.4 
Exploratory Objective  
An exploratory objective of this study is to evaluate the effect of allelic variation in CD16A, 
CD32A, and CD32B on the efficacy of margetuximab in all patients receiving study 
treatments.  
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4 
STUDY DESIGN  
4.1 
Overall Study Design and Plan  
4.1.1 
Study Design  
This is a Phase 3, randomized, open-label, comparator-controlled study comparing 
margetuximab to trastuzumab, each in combination with chemotherapy, for the treatment of 
patients with advanced HER2+ breast cancer who have received at least 2 prior lines of 
anti-HER2 directed therapy in the metastatic setting, or in case of having received 
(neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the 
metastatic setting, and who have received at least one, and no more than three, lines of 
therapy overall in the metastatic setting. Patients must have progressed on or following the 
most recent therapy. Eligible patients will be assigned to chemotherapy of the investigator’s 
choice to be chosen from capecitabine, eribulin, gemcitabine, or vinorelbine. The selected 
chemotherapy must be allowed for use per local regulations; see Section 6.1.2 for additional 
information. Upon meeting all entry criteria, patients enrolled in the study will be 
randomized 1:1 to receive either margetuximab or trastuzumab to be administered in 
combination with the chosen chemotherapy. Patients will be treated until disease progression, 
death, withdrawal of consent, or request by the treating physician to discontinue treatment. 
Following completion of (or discontinuation from) treatment, patients will be followed for 
survival.  
4.1.1.1 
Infusion Sub-Study  
The sub-study will start with a run-in group to evaluate the safety and tolerability of reduced 
infusion times. About 9 patients will receive a 120-minute margetuximab infusion (as a 
single agent, or in combination with protocol-specified chemotherapy) in Cycle 1, in order to 
have 6 patients receive a 60-minute infusion in Cycle 2 and beyond (Stage A1). If no 
stopping rules are met, an additional cohort of about 9 patients will be enrolled to receive a 
120-minute margetuximab infusion in Cycle 1, in order to have 6 patients receive a 30-
minute infusion at Cycle 2 and beyond (Stage A2). Patients enrolled into Stage A1 and A2 
will be assigned to receive the reduced infusions until 6 patients have received reduced 
infusion times. Any extra patients beyond 6 in run-in groups A1 or A2 will continue 120-
minute infusions until the Stage B regimen is confirmed. In the absence of Grade 3 or higher 
IRRs, patients in Stage A may reduce infusion duration to the Stage B regimen.   
Safety events observed in Stage A1 and A2 will be used to inform infusion reduction 
schemes for a subsequent group of about 60 patients enrolled to Stage B, who will receive 
margetuximab over a 120-minute infusion in Cycle 1, followed by either a 60-minute or 30-
minute infusion in Cycles 2 and beyond. Details of the study design and stopping rules can 
be found in Section 6.7.1, and Figure 1.   
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The backbone chemotherapies to be used during this study are described in Section 6.1.2. 
4.1.2.2 
Study Drugs  
Following enrollment and selection of chemotherapy, patients will be randomized 1:1 to 
receive either margetuximab or trastuzumab. Randomization will be stratified by number of 
metastatic sites (≤2, >2), number of lines of therapy overall in the metastatic setting (≤2, >2), 
and choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Patients 
will receive either margetuximab or trastuzumab on Day 1 of a 3-week cycle. Chemotherapy 
will be administered according to the schedule of the chosen agent beginning on Day 1 and 
will be given prior to margetuximab or trastuzumab on days when both study drug and 
chemotherapy are to be administered.  
The study drugs (margetuximab and trastuzumab) to be administered during this study are 
described in Section 6.1.1.  
4.1.3 
Dose Delays  
For patients who experience toxicity due to backbone chemotherapy and the investigator 
deems it necessary to hold the chemotherapy treatment, treatment with study drug should 
continue without delay. Chemotherapy treatment should be reinstituted at the next scheduled 
dose for that chemotherapeutic agent, once toxicity has improved or resolved. Any toxicity 
that leads to delay in study drug treatment, reinstitution of the study drug at the next 
scheduled dose of the study drug is recommended. Delays of up to 28 days are allowed, after 
which patients are discontinued from treatment. For patients who specifically experience a 
drug-related decrease in cardiac function, guidance on dose delays is provided in Sections 
6.1.1.1.1 and 6.1.1.2.1. 
4.1.4 
Disease Assessments  
Patients will be evaluated at regular intervals for disease status as described in 
Section 7.10.1.1 and Appendix 1 (Schedule of Events). Computed tomography (CT) and/or 
magnetic resonance imaging (MRI) scans will be performed prior to treatment (baseline) and 
every 2 cycles for the first 24 weeks of treatment. Thereafter, beginning with Cycle 9, tumor 
evaluation will be performed every 4 cycles while on treatment or every 3 months during 
post-treatment follow-up until documented disease progression, initiation of alternative anti-
cancer therapy, lost to follow-up, withdrawal of informed consent, death, or the end of study. 
Bone scans will be performed on all patients at baseline and then as clinically indicated for 
the assessment of bone metastasis. Disease response will be determined both locally and by 
central review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. With 
Protocol Amendment 4, central review of radiographic images will be discontinued. 
Investigator-assessed PFS and ORR will continue to be assessed according to the protocol 
schedule.  
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Patient treatment decisions will be based on local (investigator) reviews of available 
assessments. Central reviews will be blinded to study treatment (margetuximab or 
trastuzumab) and will be used only for the primary endpoint analysis of PFS.  
4.1.5 
Rules for Continuation of Study Treatment  
Patients who tolerate the combination therapy may continue on study until disease 
progression or as otherwise determined by the investigator. Patients who are intolerant of the 
chosen backbone chemotherapy, but do not exhibit signs of disease progression should 
continue on margetuximab or trastuzumab alone. At the investigator’s discretion, patients 
who have received at least 6 cycles of treatment and who do not exhibit disease progression 
may have chemotherapy discontinued but remain on trastuzumab or margetuximab alone. 
Post-progression margetuximab may be considered on a case-by-case basis, with agreement 
of the Sponsor’s medical monitor, for infusion sub-study patients only. 
See Section 5.4.1 for additional criteria requiring withdrawal from study treatment.  
4.2 
Rationale for Study Design  
Therapy directed against HER2, either via a monoclonal antibody or derivatives or by small 
molecule inhibition has shown efficacy in patients with advanced breast cancer. To date, no 
HER2-targeted agents have been approved in the US to specifically treat patients after two 
prior lines of treatment, although both lapatinib and trastuzumab are often used in this 
setting. The purpose of this study is to evaluate the activity of margetuximab in combination 
with standard of care chemotherapies in the setting of patients with metastatic HER2+ breast 
cancer who have received at least 2 prior lines of anti-HER2 directed therapy in the 
metastatic setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior 
line of anti-HER2 directed therapy in the metastatic setting, and who have received at least 
one, and no more than three, lines of therapy overall in the metastatic setting. Because 
common practice is to treat these patients with an anti-HER2 agent in combination with 
chemotherapy, it is unethical to compare the effect of margetuximab with placebo, and 
therefore an active comparator was chosen. Trastuzumab is commonly used in this setting, 
and the comparison will directly evaluate whether a molecule that has been engineered to 
enhance ADCC produces superior clinical efficacy. Although not approved in this setting, 
trastuzumab is an acceptable comparator because continued treatment with trastuzumab after 
failure while on trastuzumab has demonstrated clinical benefit. In addition, trastuzumab has a 
generally favorable toxicity profile compared with lapatinib, and is commonly used in 
clinical practice (4, 19). 
The decision to allow physician’s choice of chemotherapy from among a selected list is 
based on the well-described finding (7) that, in the treatment of advanced breast cancer, 
sequential single agent chemotherapies are superior to combination therapy, and that, other 
than eribulin - which showed a modest survival benefit - no one agent has been clearly shown 
to be superior to another in the salvage setting. Common practice is to choose a therapy 
based on individual patient needs and combine that with trastuzumab. Rather than dictate the 
therapy, investigators will choose the patient’s combination chemotherapy from a 
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predetermined list, allowing for a tailored approach to each individual patient’s status (also 
similar to the control arm in the eribulin pivotal study (6)). To minimize bias, the selected 
chemotherapy will be chosen and documented prior to patient randomization. 
See Section 2.2.1, which details the rationale of modifying eligibility criteria as of 
Amendment 2 to enroll patients with metastatic HER2+ breast cancer who have received at 
least 2 prior lines of anti-HER2 directed therapy in the metastatic setting, or in case of having 
received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the 
metastatic setting, and who have received at least one, and no more than three, lines of 
therapy overall in the metastatic setting. 
See Section 2.2.2, which explains the rationale for the infusion sub-study.  
4.3 
Study Duration  
It is anticipated that this study will take 24 months to enroll at worldwide sites. An additional 
16 months will be required to accrue the 385 survival events necessary for determination of 
the hazard ratio based on pre-study estimates of PFS and OS for margetuximab and 
trastuzumab, for a total estimated study duration of approximately 40 months. An interim 
analysis for futility based on PFS will be performed after a total of about 100 PFS events 
have occurred. The first primary endpoint of PFS will be evaluated after approximately 
257 PFS events have occurred or after all patients have been randomized, whichever occurs 
later.  
4.3.1 
Patient Accrual  
After obtaining informed consent and conducting pre-study eligibility assessments, eligible 
patients will be enrolled and randomized in a 1:1 fashion to receive either margetuximab or 
trastuzumab in combination with the pre-determined choice of chemotherapy. Accrual will 
continue until approximately 530 patients have been enrolled and randomized or 385 survival 
events have occurred, whichever occurs first.  
Infusion Sub-Study: Up to about 78 patients will be accrued to the study in a non-
randomized fashion. Accrual will continue until stopping rules are met or the sub-study is 
complete.   
4.3.2 
Definition of End of Study  
The end of this study is defined as when the last patient visit occurs or one year after the final 
survival analysis, whichever occurs first. Patients experiencing clinical benefit with 
margetuximab treatment at the end of the study may be allowed to continue margetuximab 
treatment supplied by the study Sponsor. Continued treatment with trastuzumab at the end of 
the study must be sourced by the study investigator/treating physician and will not be the 
responsibility of the study Sponsor, unless required by local/site regulations.  
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5 
SELECTION AND WITHDRAWAL OF PATIENTS  
Inclusion and exclusion criteria are designed to properly define the target population for 
study participation and to identify those patients who may not be appropriate candidates for 
study participation based on specific co-morbidities or other clinicopathologic features of 
their disease. Patients must meet all of these criteria to be eligible for study participation; no 
exceptions to these criteria will be granted by the Sponsor.  
5.1 
Inclusion Criteria  
To be included in this study, patients must: 
General 
1. Be able 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 and completion of HRQoL assessments.  
2. Be ≥ 18 years old. Patients may be male or female. 
3. Have histologically proven metastatic or locally advanced relapsed/refractory 
HER2+ (3+ by IHC or ISH-amplified as per American Society of Clinical 
Oncology [ASCO] and the College of American Pathologists [CAP] Guidelines) 
breast cancer based on the most recently available tumor biopsy collected from the 
patient. HER2 status must be documented from a reference laboratory that 
conforms to standards set for accreditation by CAP or an equivalent accreditation 
authority. Confirmatory IHC testing is not required for study entry. Tumors may be 
estrogen receptor (ER)/progesterone receptor (PgR) positive or negative. 
4. Have received at least 2 prior lines of anti-HER2 directed therapy in the metastatic 
setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior 
line of anti-HER2 directed therapy in the metastatic setting. In either case, patients 
must have received prior treatment with pertuzumab in the (neo)adjuvant or 
metastatic setting. Prior radiotherapy, hormonal therapies, and other anti-HER2 
therapies are allowed.  
5. Have received treatment for at least one, and no more than three, lines of therapy 
overall in the metastatic setting. Hormonal therapies will not be considered when 
determining the number of previous lines of therapy in the metastatic setting. Prior 
neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of 
completion of therapy will be considered a line of treatment for metastatic disease. 
Eligible patients must have progressed on or following, the most recent line of 
therapy. Dose interruptions, delays, pauses during previous therapy, or changes in 
therapy to manage toxicity will not constitute a new line of therapy provided 
disease progression did not occur.  
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6. Resolution of all chemotherapy or radiation-related toxicities to ≤ Grade 1 (with 
exception of ≤ Grade 2 alopecia, stable sensory neuropathy, or stable electrolyte 
disturbances that are managed by supplementation). 
7.  Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
(Appendix 4). 
8. Have life expectancy ≥ 12 weeks. 
9. Have either measurable or non-measurable disease as per RECIST 1.1 criteria and 
documented by CT and/or MRI. 
 
Laboratory Features  
10. Have acceptable laboratory parameters as follows:   
a. Platelet count  100 × 103/µL without having received a transfusion or 
growth factor support within 4 weeks prior to randomization. 
b. Hemoglobin  9.0 g/dL without having received a transfusion or growth 
factor support within 4 weeks prior to randomization. 
c. Absolute neutrophil count  1.5 × 103/µL in the absence of any growth 
factor support given within 4 weeks prior to randomization. 
d. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST)  3.0 × 
the upper limit of normal (ULN), except patients with liver metastases, 
who may enroll with ALT/AST  5.0 × ULN. 
e. Total bilirubin  1.5 × ULN, except patients with Gilbert’s syndrome, who 
may enroll if the conjugated bilirubin is within laboratory normal limits. 
f. Creatinine < 1.5 mg/dL, or a calculated or measured creatinine clearance 
> 50 mL/min. 
Reproductive Features 
11. Female patients of childbearing potential (not surgically sterilized and between 
menarche and 1-year post menopause) must have a negative result from a serum 
pregnancy test performed within 14 days of randomization and a negative serum or 
urine pregnancy test on the day of first study treatment prior to the initiation of study 
treatment.  
Further, female patients of childbearing potential must agree to use highly effective 
contraceptive measures from the time of informed consent through 7 months after the 
last dose of study drug (either margetuximab or trastuzumab). Highly effective 
methods of contraception include:  
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with the inhibition of ovulation 
o Oral 
o Intravaginal 
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o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence 
 
12. Male patients should also have their partners who are women of childbearing 
potential use a highly effective method of contraception (as shown above) from the 
time of informed consent through 7 months after last dose of study drug (either 
margetuximab or trastuzumab).  
5.2 
Exclusion Criteria  
Patients who meet any of the following criteria will be excluded from the study: 
1. Patients with known, untreated brain metastasis.  
• Patients with signs or symptoms of brain metastasis must have a CT or MRI 
performed within 4 weeks prior to randomization to specifically exclude the 
presence of radiographically detectable brain metastases.  
• Patients with known, treated brain metastases must have a baseline CT or MRI 
within 4 weeks of randomization and are eligible provided all therapy for the 
metastases concluded at least 4 weeks prior to randomization, or, if continued 
steroid therapy is indicated following therapy, they have been on a stable dose of 
steroids (≤ 10 mg/day of prednisone or equivalent) for at least 4 weeks prior to 
randomization with no symptoms. 
2. History of uncontrolled seizures within 6 months of randomization. 
3. History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation.  
4. Treatment with any local or systemic anti-neoplastic therapy (including hormonal 
therapies for breast cancer) or any investigational therapy within 2 weeks prior to 
randomization. Bisphosphonates and receptor activator of nuclear factor kappa B 
ligand (RANKL) inhibitors are allowed provided treatment starts prior to 
randomization. 
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5. Treatment with corticosteroids (i.e., > 10 mg prednisone per day or equivalent) or 
other immune suppressive drugs within 2 weeks prior to randomization. Steroids 
for topical use, inhalational use, nasal spray, or ophthalmic solution are allowed. 
6. History of clinically significant cardiovascular disease including but not limited to:  
a. Myocardial infarction or unstable angina within 6 months prior to 
randomization.  
b. Stroke or transient ischemic attack within 6 months prior to randomization. 
c. Clinically significant cardiac arrhythmias. 
d. Uncontrolled (persistent) hypertension defined as systolic blood pressure 
(SBP) >180 mmHg or diastolic blood pressure (DBP) >100 mmHg. 
e. Congestive heart failure (New York Heart Association [NYHA] class II-IV). 
f. Pericarditis or clinically significant pericardial effusion. 
g. Myocarditis. 
h. LVEF < 50% by echocardiogram or multi-gated acquisition (MUGA) scan. 
7. Clinically significant pulmonary compromise, including a requirement for 
supplemental oxygen use to maintain adequate oxygenation. 
8. Evidence of active viral, bacterial, or systemic fungal infection requiring 
parenteral treatment within 7 days prior to randomization.  
9. Known positive testing for human immunodeficiency virus or acquired immune 
deficiency syndrome. 
10. Active hepatitis B or hepatitis C infection or known positive test for hepatitis B 
surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction 
(PCR).  
11. Second primary malignancy that has not been in remission for at least 2 years from 
the anticipated start of study treatment. Exceptions of treated malignancies that do 
not require a 2-year remission include: non-melanoma skin cancer; cervical 
carcinoma in situ; squamous intraepithelial lesion; localized prostate cancer 
(Gleason score < 6); resected melanoma in situ or ductal carcinoma in situ. 
Patients with second primary breast cancers within 2 years are eligible provided 
that both primary tumors were HER2+ (3+ by IHC or in-situ hybridization [ISH] 
amplified). 
12. History of trauma or major surgery within 4 weeks prior to randomization. 
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 
investigational site. 
14. Known hypersensitivity to recombinant proteins, polysorbate 80, benzyl alcohol, 
or any excipient contained in the drug formulation for margetuximab, trastuzumab 
or other study treatments. Previous infusion reactions to trastuzumab or other 
monoclonal antibodies will not preclude enrollment provided no contraindication 
to trastuzumab therapy remains. 
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15. Any condition that would be a contraindication to receiving trastuzumab as 
described in the approved local label or a condition that would prevent treatment 
with the physician’s choice of chemotherapy. 
16. Vaccination with any live virus vaccine within 4 weeks prior to randomization. 
Inactivated annual influenza vaccination is allowed at any time. 
17. Dementia or altered mental status that would preclude understanding and 
rendering of informed consent. 
18. Active or history of alcohol or other substance abuse within 1 year prior to 
randomization. 
19. Pregnant or breast feeding. 
20. Prior participation in a margetuximab clinical study. 
21. Any investigative site personnel directly affiliated with this study. 
22. Employees of MacroGenics, Inc. 
23. Prisoners or other individuals who are involuntarily detained.  
24. Any issue or condition 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 
Entry Criteria for the Infusion Sub-Study  
1. Patients will meet all entry criteria for the randomized portion of the study with the 
exception of inclusion criteria #4 and #5.  
2. Patients must have received at least 4 prior lines of therapy for metastatic disease.  
Hormonal therapies will not be considered when determining the number of 
previous lines of therapy in the metastatic setting. Prior neo-adjuvant or adjuvant 
therapy that resulted in relapse within 6 months of the completion of therapy will 
be considered a line of treatment for metastatic disease. Eligible patients must have 
progressed on or following the most recent line of therapy. Dose interruptions, 
delays, pauses during previous therapy, or changes in therapy to manage toxicity 
will not constitute a new line of therapy provided disease progression did not 
occur. 
3. Patients must have received prior trastuzumab, pertuzumab, and T-DM1. 
5.4 
Withdrawal of Patient from the Study or Study Drug  
5.4.1 
Guidelines for Permanent Discontinuation  
Patients should be permanently withdrawn from all study treatment for any of the following 
situations. Patients who are withdrawn from the study will not be replaced. 
• Following patient enrollment and treatment, a violation of enrollment criteria or 
other significant protocol violation is discovered of such nature that continued 
treatment would not be in the best interest of the patient. 
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• Patient develops an uncontrolled intercurrent illness unrelated to cancer that 
renders continuing treatment unsafe or regular study visits impossible. 
• Patient experiences an AE or serious adverse event (SAE) that necessitates 
discontinuation of study drug (i.e., margetuximab or trastuzumab). 
• The Sponsor or Regulatory Agency terminates the study, or investigator 
terminates participation in the study.  
• The patient requests to be discontinued from the study, i.e., withdraws consent. 
• The patient is noncompliant with study drugs, chemotherapy, other study 
medication, or protocol-required evaluations. 
• Patient is withdrawn at investigator’s discretion.  
• The patient exhibits progression of disease by RECIST 1.1 criteria. 
• The patient becomes pregnant during the study. Upon confirmation of the 
pregnancy, the patient must discontinue treatment with study drug immediately.  
• Treatment delay of study drug greater than 28 days (except due to drug-related 
cardiac toxicity (see Section 4.1.3)). 
• Patient death 
The Sponsor or its designee must be notified within 24 hours of discontinuations meeting 
criteria for an Immediately Reportable Event (IRE) (Section 7.9.2.7) using the procedures 
outlined in Section 7.9.7. For all permanent discontinuations, patients will continue to be 
followed as appropriate and consistent with protocol guidelines but should receive no further 
study treatment. All patients should be followed for survival – the only exception would be 
withdrawal, by the patient, of consent.  
5.4.2 
Procedures for Patients Lost to Follow-up  
Patients will be considered lost to follow-up if no contact can be established despite repeat 
attempts to contact. Investigators must document all attempts to contact missing patients 
throughout the study period unless consent for follow-up has been withdrawn. At a 
minimum, it is expected that sites will send at least two certified letters to a missing patient to 
attempt to re-establish contact, and patients will not be considered lost to follow-up until this 
has occurred. If contact with a missing patient is re-established, resumption of study drug 
administration may be considered and must be discussed with the medical monitor prior to 
recommencement. If contact is re-established in the Post-Treatment Follow-up phase, 
evaluations should resume according to the protocol. 
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6 
STUDY TREATMENTS  
6.1 
Description of Treatment(s)  
An overview of study treatments to be administered during this study is presented in Table 4. 
On days when both the study drug and chemotherapy are to be administered, the 
chemotherapy will be administered first. 
Table 4 
Overview of Study Treatments  
Agent 
Starting Dose 
Schedule 
Mode of 
Administration 
Chemotherapya 
 
 
 
     Capecitabine 
1000 mg/m2 BID 
BID for 14 days in a 21-day cycle 
Oral 
     Eribulinb 
1.4 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
     Gemcitabine 
1000 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
     Vinorelbine 
25-30 mg/m2 
Day 1 and 8 of a 21-day cycle 
IV 
Study Drugs 
 
 
 
     Trastuzumab 
8 mg/kg loading dose then 
6 mg/kg 
Every 21 days 
IV 
     Margetuximab 
15 mg/kg 
Every 21 days 
IV 
BID = twice daily; IV = intravenous 
a 
The chemotherapy selected must be allowed for use per local regulations (see Section 6.1.2). 
Chemotherapies must be used at the protocol-indicated starting doses, schedule, and route of 
administration, however dose adjustments to improve tolerability and manage toxicities are permitted. 
b 
Dose of eribulin noted here is based on use as eribulin mesylate; if free base eribulin is used, equivalent 
dose of 1.23 mg/m2 is permitted.  
 
All changes in study drug infusions, including interruptions and their duration, as well as 
reductions in rate and duration, must be recorded. Chemotherapies are to be administered at 
the starting dose, frequency, and route indicated per protocol.  
6.1.1 
Study Drugs  
6.1.1.1 
Margetuximab  
Margetuximab will be administered on Day 1 of a 3-week cycle at a dose of 15 mg/kg via IV 
infusion over 120 minutes, unless the patient is enrolled to the infusion sub-study. On days 
when both chemotherapy and margetuximab are to be administered, the chemotherapy will 
be administered first. 
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6.1.1.1.1 
Dose Rate or Schedule Modifications for Toxicity  
The rate of margetuximab infusion or dose schedule may be modified for infusion-related 
reactions or cardiac toxicities, respectively, that are determined to be associated with 
margetuximab based on the following parameters: 
• Infusion-related reactions:  follow guidelines described in Section 6.6.2.2 
• Decreased cardiac function – withhold margetuximab for at least 4 weeks if either 
of the following criteria are met:  
o ≥ 16% absolute decrease in LVEF from pre-treatment values, or  
o LVEF below institutional normal limits (or 50% if no limits are available) 
and ≥ 10% absolute decrease in LVEF from pretreatment values 
LVEF will be monitored at regular intervals during the study. If a decrease in cardiac function 
is suspected, LVEF should be determined using the same method as used prior to treatment. 
Margetuximab may be resumed if, within 8 weeks, the LVEF returns to within normal limits 
and the absolute decrease from baseline is ≤ 15%. 
Margetuximab should be permanently discontinued if a decline in LVEF persists for 
>8 weeks or if dosing is interrupted for more than 3 occasions due to cardiomyopathy. 
Please refer to the Investigator’s Brochure for information on special warnings and 
precautions for use, interaction with other medicinal products and other forms of interaction, 
and undesirable effects associated with margetuximab. 
6.1.1.2 
Trastuzumab  
Trastuzumab will be administered via IV infusion on Day 1 of a 21-day cycle at a dose of 
8 mg/kg for the first dose (over 90 minutes) and 6 mg/kg for all subsequent doses (over 30 to 
90 minutes). On days when both chemotherapy and trastuzumab are to be administered, the 
chemotherapy will be administered first. 
Contraindications 
In addition to inclusion exclusion criteria incorporated into this protocol, the following are 
contraindications specific to the administration of trastuzumab: 
• Hypersensitivity to trastuzumab, murine proteins, or to any of the excipients. 
• Severe dyspnea at rest due to complications of advanced malignancy or requiring 
supplemental oxygen therapy. 
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6.1.1.2.1 
Dose Modification for Toxicity  
Dose reduction 
No reductions in the dose of trastuzumab should be made. Patients may continue therapy 
during periods of reversible, chemotherapy-induced myelosuppression but they should be 
monitored carefully for complications of neutropenia during this time.  
The trastuzumab package insert should be consulted for any dose modifications or 
adjustments. Trastuzumab dosing will be modified for infusion reactions and 
cardiomyopathy.  
For infusion reactions, the guidelines described in Section 6.6.2.2 should be followed. 
Trastuzumab should be withheld for at least 4 weeks if a decrease in cardiac function as 
follows is observed: 
• ≥ 16% absolute decrease in LVEF from pre-treatment values, or  
• LVEF below institutional normal limits and ≥ 10% absolute decrease in LVEF 
from pretreatment values 
If LVEF has not improved, or declined further, or symptomatic congestive heart failure 
(CHF) has developed, discontinuation of trastuzumab should be strongly considered, unless 
the benefits for the individual patient are deemed to outweigh the risks. All such patients 
should be referred for assessment by a cardiologist and followed up. 
LVEF will be monitored at regular intervals during the study. If a decrease in cardiac function 
is suspected, LVEF should be determined using the same method as used prior to treatment. 
Trastuzumab may be resumed if, within 8 weeks, the LVEF returns to within normal limits 
and the absolute decrease from baseline is ≤ 15%. 
Trastuzumab should be permanently discontinued if a decline in LVEF persists for > 8 weeks 
or if dosing is interrupted for more than 3 occasions due to cardiomyopathy.  
6.1.2 
Backbone Chemotherapy  
The choice of backbone chemotherapy will be made by the treating physician prior to 
randomization. The choice of therapy should be made based on the patient’s co-morbidities 
and the physician’s best judgment about the most appropriate chemotherapy for a given 
patient. Chemotherapies must be used at the protocol-indicated starting doses, schedule, and 
route of administration (see Table 4); however, dose adjustments to improve tolerability and 
manage toxicities are permitted. Allowable chemotherapeutic agents include capecitabine, 
eribulin, gemcitabine, and vinorelbine (except in Italy where sites can choose from 
capecitabine and vinorelbine only per local requirements). The chemotherapy selected must 
be allowed for use per local regulations and will be supplied locally unless an alternate 
source for the selected agent is needed. Changes in backbone chemotherapy will not be 
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allowed following patient randomization (see Section 4.1.2.1). Substitution of generic 
equivalents for branded products is acceptable if such products have been approved by local 
regulatory authorities for use in the treatment of human diseases. Substitution of different 
doses due to differences in formulation is allowed provided that the amount of active drug 
substance is equivalent. The use of therapies other than those used to treat or prevent 
toxicities, either alone or in combination with either of the 4 allowed chemotherapy agents, is 
not allowed.  
Dose modifications for toxicities associated with chemotherapy agents should be managed 
according to instructions provided within each product’s respective package insert. 
If used in the infusion sub-study, backbone chemotherapy will be administered according to 
the same protocol-specified direction for the randomized cohorts. 
6.2 
Study Drugs and Supplies  
6.2.1 
Margetuximab  
Margetuximab is a sterile, clear-to-slightly-opalescent, colorless-to-pale-yellow or 
pale-brown, preservative-free solution for IV administration. Margetuximab will be supplied 
at a protein concentration of 25 mg/mL in a single-use vial containing 250 mg/10 mL. 
Margetuximab is packaged in US Pharmacopeia (USP) and Ph. Eur. Conforming Type I 
borosilicate, 10 mL clear glass vials with FluroTec® coated 4432/50 gray butyl rubber serum 
stoppers and aluminum seals with plastic overseals. The product is formulated in a buffer 
containing 1.1 mg/mL sodium phosphate monobasic, monohydrate, 0.58 mg/mL sodium 
phosphate dibasic, heptahydrate, 2.9 mg/mL sodium chloride, 11 mg/mL L-arginine 
hydrochloride, 30 mg/mL sucrose, and 0.1 mg/mL Polysorbate 80, pH 6.1. Requests for 
additional study drug should be made to MacroGenics, Inc., via Interactive Response System 
(IxRS) at least 2 weeks in advance. 
6.2.2 
Trastuzumab  
Trastuzumab (marketed as HERCEPTIN® by Genentech, Inc., A Member of the Roche 
Group, 1 DNA Way, South San Francisco, CA 94080-4990; Made in Switzerland by F. 
Hoffmann-La Roche Ltd, Basel) is available as follows: 
• 440 mg vial is supplied in a multi-use vial containing 440 mg trastuzumab as a 
lyophilized sterile powder, under vacuum. Each carton contains one vial 
trastuzumab and one vial (20 mL) of Bacteriostatic Water for Injection, USP, 
containing 1.1% benzyl alcohol as a preservative. Though supplied as a multi-use 
vial, each vial may only be used once.  
• 150 mg vial is supplied in a single-dose vial containing 150 mg trastuzumab as a 
white lyophilized powder for preparation of a concentrated solution for infusion. 
Each carton contains one vial trastuzumab 150 mg. 
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6.2.3 
Backbone Chemotherapies  
Backbone chemotherapies will be provided locally unless an alternate source for the selected 
agent is needed. 
6.3 
Drug Preparation and Administration  
6.3.1 
General Precautions  
The calculated dose for chemotherapy and margetuximab or trastuzumab will be 
administered based on the patient’s actual weight at Cycle 1 Day 1 (baseline). Significant 
(≥ 10%) change in body weight from baseline should prompt recalculation of dose. For body 
surface area (BSA) determination, a change in weight of ≥10% will prompt recalculation of 
BSA and dose according to institutional standards. 
Backbone chemotherapies and trastuzumab should be prepared and administered according 
instructions provided within each product’s respective package insert. 
Infusion or allergic reactions may occur with the infusion of monoclonal antibodies and other 
protein-based therapeutics. Precautions for anaphylaxis should be observed during 
margetuximab and trastuzumab administration. Supportive measures may include, but are not 
limited to: epinephrine, antihistamines, corticosteroids, IV fluids, vasopressors, oxygen, 
bronchodilators, diphenhydramine, and acetaminophen. Please refer to Section 6.6.2.2 for 
specific guidelines regarding the management of infusion reactions. Supportive care 
measures consistent with optimal patient care will be provided throughout the study 
according to institutional standards. 
6.3.2 
Margetuximab Preparation  
Recommended safety measures for handling and preparation include masks, protective 
clothing, gloves, and vertical laminar airflow safety cabinet. 
Before administration, parenteral drug products should be inspected visually. Some visible, 
translucent, proteinaceous, margetuximab particles may be present. However, if foreign 
particulate matter or discoloration is observed, the drug should not be administered. The 
desired amount of margetuximab should be withdrawn from the vial(s) and diluted in a 
250 mL polyolefin (e.g., polypropylene) or olefin copolymer (e.g., ethylene and propylene 
copolymer) (hereafter referred to collectively as “olefin polymer/copolymer”), or polyvinyl 
chloride (PVC) infusion bag containing 0.9% Sodium Chloride Injection, USP at a final 
concentration of 2.4 to 7.2 mg/mL. The bag should be appropriately labeled and gently 
inverted to mix the solution. THE BAG MUST NOT BE SHAKEN; excessive agitation may 
cause aggregate formation. A low protein binding polyethersulfone (PES) 0.2 micron filtered 
administration set must always be used for IV administration of margetuximab. 
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Since margetuximab does not contain preservatives, once diluted in normal saline, 
administration should begin immediately after preparation but can be stored at 2° to 8°C for 
up to 6 hours after preparation. 
Margetuximab should not be administered as an IV push or bolus. Margetuximab should not 
be mixed or diluted with other drugs. Vials are single unit-dose containers. Any partially used 
vials or diluted dosing solutions should be discarded using appropriate drug disposal 
procedures. 
6.3.3 
Study Drug and Chemotherapy Administration  
Margetuximab will be administered as a 120-minute (2-hour) IV infusion after chemotherapy 
administration for patients in the randomized cohorts. Margetuximab may be administered 
after completion of chemotherapy administration. Two consecutive doses should be a 
minimum 18 days apart. 
For patients randomized to trastuzumab, the first dose will be administered as a 90-minute 
infusion after chemotherapy administration. For subsequent doses, trastuzumab will be 
administered as a 30-90-minute IV infusion. Trastuzumab may be administered after 
completion of chemotherapy administration. Two consecutive doses should be a minimum 
18 days apart. 
Chemotherapies will be administered as described in Table 4 and per each individual agent’s 
prescribing information.  
The chosen chemotherapy (if administered IV) and randomized study drug must be 
administered within ± 10 minutes of the indicated infusion duration.  
6.3.3.1 
Premedications and Prophylaxis for Chemotherapy  
Standard premedications for the administration of the cytotoxic chemotherapy will be 
employed in the study. For chemotherapy, recommendations made in the locally approved 
label should be followed for each agent. 
6.3.3.2 
Premedications for Margetuximab  
When margetuximab infusions coincide on the same day with cytotoxic chemotherapy 
administration, the premedications for the chemotherapy should be employed and should be 
sufficient for prophylaxis of margetuximab infusion reactions as well. 
Premedication is not required, but the following recommendations are made regarding 
premedications for margetuximab administration on those days upon which that 
administration is not preceded by a chemotherapeutic agent or if no premedication is 
employed for that chemotherapy. Premedication should be given within 30 minutes of 
margetuximab administration if it has not previously been administered prior to backbone 
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chemotherapy. These recommendations should serve as guidelines and may be modified by 
the Investigator. 
Prior to the infusion: 
• Acetaminophen 650-1000 mg orally (PO) or ibuprofen 400 mg PO 
• Diphenhydramine 50 mg PO or IV or equivalent H1 antagonist 
• Ranitidine 300 mg PO or IV or equivalent H2 antagonist 
• Dexamethasone 10 mg IV or equivalent (for patients at high risk) 
 
6.3.3.3 
Premedications for Trastuzumab  
There are no premedications specified for administration of trastuzumab (See most current 
Herceptin Prescribing Information). Dose modifications for toxicity are described in 
Section 6.1.1.2.1.  
6.3.4 
Additional Instructions for Handling  
Margetuximab or trastuzumab should not be mixed or diluted with other drugs. Any partially 
used vials or diluted dosing solutions should be discarded using appropriate drug disposal 
procedures. Although trastuzumab may be supplied in a multi-use vial, each vial may only be 
used once during this study. 
6.4 
Dispensing Study Drug  
Under no circumstances is the investigator allowed to release the clinical study drug supplies 
for use by another physician not named on Form FDA 1572 (or equivalent document) or 
administer study drug to a patient who is not enrolled in this study. Study drug must be 
dispensed at an institution specified on Form FDA 1572 (or equivalent document). 
6.5 
Selection and Timing of Dose for Each Patient  
Patients will be randomized 1:1 to receive either margetuximab or trastuzumab, both in 
combination with chemotherapy preselected by the investigator. Randomization will be 
stratified by number of metastatic sites (≤ 2, > 2), number of lines of therapy in the metastatic 
setting (≤2, >2), and choice of chemotherapy (capecitabine, eribulin, gemcitabine, or 
vinorelbine). Study drug (margetuximab or trastuzumab) will be administered after 
chemotherapy drugs are administered on Day 1 of each 3-week cycle. 
6.5.1 
Selection and Timing of Infusion Sub-Study Patients  
Patients who participate in the infusion sub-study will not be stratified nor randomized. They 
will be enrolled to receive either monotherapy margetuximab or margetuximab in 
combination with protocol-specified (Table 4) physician choice chemotherapy, at the 
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discretion of the investigator. Margetuximab will be administered on Day 1 of each 3-week 
cycle, after the chemotherapy if combination therapy is chosen. 
6.6 
Potential Adverse Events and Supportive Care Measures  
6.6.1 
Study Drugs (Margetuximab and Trastuzumab)  
Supportive care measures specific to trastuzumab and margetuximab are described below; 
recommended modifications for toxicity specific to these agents are provided in 
Section 6.1.1. 
6.6.2 
Infusion Related Reactions  
Infusion-related reactions including 
hypersensitivity/anaphylactic/anaphylactoid reactions may occur.  
Precautions for the management of these reactions should be observed  
during margetuximab and trastuzumab administration. 
Infusion reactions associated with margetuximab or trastuzumab administration should be 
managed according to the standard practice of medicine. General guidelines for the 
management of such reactions are provided in this section.  
Patients should be monitored closely for the development of infusion-related reactions during 
margetuximab or trastuzumab infusion. Medications and supportive measures for the 
treatment of severe hypersensitivity reactions should be available for immediate use for an 
infusion reaction 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 25-100 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 also 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 whether the 
cause of the symptoms is related to emerging infection or infusion reaction. As such, patients 
should be evaluated carefully for the presence of infection, with the acquisition of cultures 
and/or implementation of empiric antibiotic therapy as appropriate based on the assessment 
of the Investigator. Please refer to Section 6.6.2.2 for guidance regarding the management of 
infusion reactions.  
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6.6.2.1 
Grading of Infusion Reactions  
Infusion reactions will be categorized as follows: 
• Grade 1:  mild reaction; infusion interruption not indicated, intervention not 
indicated. Note: although interruption in infusion is not indicated, temporary rate 
reduction is indicated before resuming the original infusion rate, as tolerated by 
the patient (see Section 6.6.2.2); 
• 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. 
Guidelines regarding premedications for the prevention of infusion reactions are provided in 
Section 6.3.3.2. Investigators are encouraged to intervene early and vigorously in the 
treatment of infusion reactions and cytokine release syndrome if they occur.  
6.6.2.2 
Management of Observed Margetuximab or Trastuzumab 
Infusion Reactions  
The following are treatment guidelines (which may be modified as needed by the responsible 
investigator according to the best practices of medicine) for margetuximab or trastuzumab 
infusion reactions: 
• Grade 1: 
o Slow the infusion rate by 50% 
o Monitor the patient for worsening of condition. 
o Continue rate at 50% reduction and increase dose rate to the original rate 
by doubling the infusion rate after 30 minutes, as tolerated. 
• Grade 2: 
o Stop the infusion. 
o Administer diphenhydramine hydrochloride 25-50 mg IV, ibuprofen 400 
mg or institutional equivalent orally for fever, and oxygen and 
bronchodilators for mild bronchospasm. 
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o Resume the infusion at 50% of the prior rate once the infusion reaction has 
resolved or decreased to Grade 1. The rate may then be escalated to the 
original rate after 30 minutes, as tolerated. 
o Monitor for worsening condition. 
o For patients with Grade 2 infusion reactions despite premedication, 
corticosteroids (hydrocortisone 100 mg IV or equivalent) should be 
considered for acute management of the event. Dexamethasone 10 mg IV 
should be added to the premedication regimen for subsequent dosing of 
margetuximab or trastuzumab at the discretion of the investigator.  
• Grade 3: 
o STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING 
FROM THE PATIENT. 
o TO AVOID EXACERBATION OF INFUSION REACTION: DO NOT 
FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG FROM THE 
PORT LUMEN. 
o Administer diphenhydramine hydrochloride 25-50 mg IV, hydrocortisone 
100 mg IV (or equivalent), and other medications/treatment as medically 
indicated. Higher doses of corticosteroids (i.e. dexamethasone 10 mg IV) 
may also be considered for acute management.  
o IV fluids, supplemental oxygen and bronchodilators should be considered 
as appropriate.  
o If symptoms have resolved to baseline within 6 hours, a rechallenge may 
be considered at the next scheduled dose, with a 50% reduction of infusion 
rate. In addition, patients should be premedicated for this rechallenge and 
for any subsequent doses of margetuximab or trastuzumab, per the 
premedication guidelines in Section 6.3.3.2 and Section 6.3.3.3. Patients 
who have a Grade 3 infusion reaction that does not resolve within 6 hours 
despite medical management should not receive further margetuximab or 
trastuzumab treatment. 
o Patients who experience a second Grade 3 infusion reaction at the time of 
rechallenge (irrespective of duration), should not receive further 
margetuximab or trastuzumab.  
o Report as an immediately reportable event (IRE) within 24 hours. 
o Report the event as an SAE, if appropriate. 
• Grade 4: 
o STOP THE INFUSION AND DISCONNECT THE INFUSION TUBING 
FROM THE PATIENT. 
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o TO AVOID EXACERBATION OF INFUSION REACTION OR CRS: 
DO NOT FLUSH THE TUBING – ASPIRATE RESIDUAL DRUG 
FROM THE PORT LUMEN. 
o Administer diphenhydramine hydrochloride 50 mg IV, dexamethasone 10 
mg IV (or more as considered appropriate), and other 
medications/treatment as medically indicated (e.g., an IL-6 receptor 
inhibitor or IL-6 inhibitor, an IL-2 receptor inhibitor, and/or an anti-TNF 
antibody). 
o Give epinephrine or bronchodilators as indicated. 
o Support ventilation and blood pressure as indicated. 
o Discontinue the patient from further margetuximab or trastuzumab. 
(Patients may remain on study and continue to receive backbone 
chemotherapy if otherwise eligible.) 
o Report as an IRE within 24 hours. 
o Report the event as an SAE.  
• Grade 5: 
o Report as an IRE within 24 hours. 
o Report the event as an SAE. 
The start time and end time of the infusion and all changes in the infusion of margetuximab 
or trastuzumab, including interruption of the infusion and overall infusion duration, as well 
as reductions in infusion rate and duration, must be recorded. The start of infusion is “0” 
time. 
6.7 
Method of Assigning Patients to Treatment Groups  
This is a randomized, comparator-control study comparing margetuximab plus chemotherapy 
to trastuzumab plus chemotherapy. Patients enrolled in the study will be stratified according 
to the number of metastatic sites (≤2, >2), number of lines of therapy in the metastatic setting 
(≤2, >2), and choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). 
Patients who meet eligibility criteria for enrollment will be randomized using IxRS within 
3 days of Study Day 1 (Cycle 1 Day 1). A central randomization scheme using permuted 
blocks will be prepared and patients will be randomized 1:1 to margetuximab plus 
chemotherapy or trastuzumab plus chemotherapy. To minimize bias, chemotherapy will be 
selected by the investigator and documented prior to patient randomization. 
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6.7.1 
Assignments in the Infusion Sub-Study  
The sub-study will start with a safety run-in group.   
Stage A1 
A cohort of about 9 patients will receive margetuximab as a 120-minute infusion time in 
Cycle 1. Of the subjects completing Cycle 1, 6 patients will go on to receive a 60-minute 
infusion time in Cycle 2 and beyond. Patients will be allocated to the reduced infusion time 
in order of their completion of Cycle 1 of treatment. Any remaining subjects in the cohort 
will continue to receive 120-minute infusions. If 2 or more patients in Stage A1 experience a 
Grade 3 or higher IRR during Cycle 2, the infusion acceleration will be abandoned and 
enrollment into the sub-study will be stopped. If no more than 1 of the 6 patients in Cycle 2 
of Stage A1 experiences a Grade 3 or above IRR, an additional 9 patients will be enrolled to 
Stage A2.  
Stage A2 
As in Stage A1, about 9 patients will receive margetuximab infused at 120 minutes in 
Cycle 1. Six patients, in the order of their completion of Cycle 1, will go on to receive a 
reduced infusion time of 30 minutes in Cycle 2 and beyond. Any remaining subjects in the 
cohort will continue to receive 120-minute infusions. If no more than 1 of the 6 patients in 
Stage A2 experiences a Grade 3 or higher IRR during Cycle 2, the sub-study will enroll about 
60 patients in Stage B to receive margetuximab infused at 120 minutes in Cycle 1 followed 
by 30 minutes in Cycle 2 and beyond. If 2 or more patients in Stage A2 experience a Grade 3 
or higher IRR during Cycle 2 (30-minute infusion), patients in Stage B will be infused 
according to the method in Stage A1.   
Stage B 
Patients will be assigned to the shortest infusion schedule based on the stopping rules for 
Stages A1 and A2. In the absence of Grade 3 or higher IRRs, all patients in Stage A1 or Stage 
A2 may have a reduced infusion duration to the Stage B infusion schedule.  
Backbone chemotherapy, if used, will be administered according to the instruction in 
Section 6.1.2 and Table 4. 
6.8 
Blinding  
This is an open-label study and no blinding of site personnel or patients will be employed. 
With exception of authorized Sponsor staff and other specified individuals not directly 
involved in the conduct of this study, clinical data provided to the Sponsor will remain 
blinded with respect to treatment assignment. Independent assessment of PFS will be 
blinded. The infusion sub-study is not blinded.   
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In this open-label study, clinical data provided to the Sponsor were blinded with respect to 
treatment assignment until primary PFS analysis. Following independent blinded PFS 
assessments to support the primary endpoint, the Sponsor was unblinded.    
6.9 
Concomitant Therapy  
All concomitant medications and blood products administered during the patient’s 
participation in the study until the End of Treatment visit (or 28 days after the last dose of 
study drug, whichever occurs later) must be recorded in the patient’s source documents and 
eCRF.  
The following rules concerning concurrent treatment(s) will apply in this study: 
• Any anti-neoplastic therapies not described in this protocol, including but not 
limited to chemotherapy or other small molecules, biologics, or hormonal or 
radiotherapy, are not allowed.  
• Palliative radiotherapy is only allowed during the study treatment period for the 
treatment of bone lesions present at baseline. Radiation therapy to a new lesion 
would, per RECIST (Appendix 8), qualify as progressive disease and necessitate 
discontinuation of therapy. RECIST target lesions cannot be in the radiation field.  
• Patients may not receive other investigational drugs during the period of study 
treatment. 
• Vaccinations (with the exception of the annual inactivated influenza vaccine) are 
prohibited during study treatment. 
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. 
• Bisphosphonates or RANKL inhibitors provided such agents are approved in the 
local jurisdiction and treatment with the agent is begun before the start of study 
treatment. 
• Use of granulocyte colony stimulating factor, granulocyte-macrophage colony 
stimulating factor or other growth factors is allowed per local practice. 
• Transfusions such as red blood cells and platelets are permitted to treat symptoms 
or signs of anemia or thrombocytopenia and should be documented on the 
concomitant medication form. 
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6.10 
Restrictions  
6.10.1 
Prior Therapy  
Prior therapy restrictions are described in the inclusion/exclusion criteria specified in 
Section 5, Selection and Withdrawal of Patients. 
6.10.2 
Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake by the 
patients during the study, although it is recommended that, to the extent possible, patients 
have a fluid intake of  2 liters on days associated with PK sampling, and that ECGs will be 
obtained pre-meal.  
6.10.3 
Patient Activity Restrictions  
There are no restrictions on patient activities and no requirement for patient confinement 
during the study. 
6.11 
Treatment Compliance  
Study drugs and backbone chemotherapy of the investigator’s choice will be administered by 
healthcare professionals under the supervision of the investigators. Records of dose 
calculation, administration, and dosing regimen will be accurately maintained by site staff for 
all administered therapies. A site study monitor, designated by the Sponsor, will review dose 
calculation, study drug administration and regimen, as well as medication accountability, 
during investigator site visits and at the completion of the study. 
6.12 
Packaging and Labeling  
Chemotherapies will be obtained locally unless an alternate source for the selected agent is 
needed. 
Margetuximab will be supplied in single-use vials. Normal saline in 250-mL IV bags will be 
obtained from the institution’s usual commercial supplier for the dilution of margetuximab 
solution for administration. All investigational products will be labelled according to local 
regulatory health authority requirements. Please see the Pharmacy Manual for detailed 
information about the packaging of margetuximab. 
Trastuzumab (marketed as HERCEPTIN® by Genentech, Inc., A Member of the Roche 
Group, 1 DNA Way, South San Francisco, CA 94080-4990; Made in Switzerland by 
F. Hoffmann-La Roche Ltd, Basel) is available as follows: 
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• 440 mg vial is supplied in a multi-use vial containing 440 mg trastuzumab as a 
lyophilized sterile powder, under vacuum. Each carton contains one vial 
trastuzumab and one vial (20 mL) of Bacteriostatic Water for Injection, USP, 
containing 1.1% benzyl alcohol as a preservative. 
• 150 mg vial is supplied in a single-dose vial containing 150 mg trastuzumab as a 
white lyophilized powder for preparation of a concentrated solution for infusion. 
Each carton contains one vial trastuzumab 150 mg.  
Trastuzumab (marketed as HERCEPTIN®) will be provided in the commercial packaging 
taken from commercial supply. Trastuzumab will be appropriately labeled and will comply 
with local legal requirements, as required. Please see the Pharmacy Manual for detailed 
information about the packaging and labeling of the trastuzumab.  
Prepared margetuximab/trastuzumab IV bags should be labeled for administration per the 
institution’s guidelines. 
6.13 
Storage and Accountability  
Chemotherapies and trastuzumab will be stored and accounted for according to institutional 
guidelines and procedures, and according to the respective Prescribing Information. 
Trastuzumab must be stored at 2−8°C (36−46°F) prior to reconstitution. 
Vials containing margetuximab must be stored under refrigeration at 2° to 8°C (36° to 46°F) 
and must not be frozen, and in an appropriate locked room accessible only to the pharmacy 
personnel or a duly designated person. Protect margetuximab from light during storage. Do 
not shake margetuximab vials. To ensure compliance, temperature logs will be maintained. 
The refrigerator must have a digital min/max thermometer or a continuous recording device. 
Administration should begin immediately after preparation of the margetuximab solution and 
no later than 6 hours after preparation when stored at 2° to 8°C. 
Accurate accounting of all study medication must be maintained. The Investigator agrees to 
keep an inventory of all study drugs received and used during the course of the study using 
the institution’s drug accountability logs or logs provided by MacroGenics. Drug disposition 
records must be kept in compliance with applicable guidelines and regulations. 
A Pharmacy Manual will be provided to the investigator or designee. When the study is 
completed, copies of all study drug accountability records must be provided to the Sponsor. 
Original drug accountability records must be maintained with study-related documentation 
for inspection by the study monitors. Additional details regarding storage, handling, and 
accountability can be found in the Pharmacy Manual. 
6.14 
Investigational Product Disposition at End of Study  
Upon completion or termination of the study, all unopened vials of study drugs must be 
returned to MacroGenics or its representative, unless the site has received written 
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authorization from MacroGenics to destroy study drug at the site. All drug returns to 
MacroGenics must be accompanied by the appropriate documentation and be clearly 
identified by protocol number and study site number on the outermost shipping container. If 
MacroGenics approves the destruction of study drug at the site, the investigator must ensure 
arrangements are made for proper disposal and that appropriate records of disposal are 
documented and maintained and copies provided to the Sponsor. 
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7 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. The Schedule of Events (Appendix 1) details the schedule of assessments by 
study visit.  
7.1 
Informed Consent  
The Investigator is responsible for ensuring that the patient or his/her legal representative 
provides informed consent prior to performing any study-related assessments, evaluations, or 
procedures. Informed consent for this study must be provided by signing an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed consent 
document (Consent for Study Participation). A copy of the 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. 
7.2 
Medical History  
A complete medical history should be obtained during the Screening period. All concurrent 
medical conditions experienced during the last 60 days and any significant prior medical 
conditions (e.g., hospitalizations, surgeries, prior cancer history) should be collected. Any 
untoward event that occurs during the Screening period (prior to first dose of any study drug) 
should be recorded as concurrent medical history and not as an AE unless it is due to a 
protocol-related procedure. Any untoward event that occurs following the first dose of study 
drug (margetuximab or trastuzumab) should be collected as an AE. 
7.3 
Prior and Concomitant Medications  
All concomitant medications and blood products administered during the patient’s 
participation in the study until the End of Treatment visit (or 28 days after the last dose of 
study drug, whichever occurs later) must be recorded in the source document and on the 
eCRF. To the extent possible, patients who receive anti-cancer agents, either approved or 
experimental, after removal from study treatment should have this information recorded in 
the eCRF, including the name of the agent and the duration of exposure. 
Prior courses of chemotherapy will be documented in the medical records and on the eCRF.  
7.4 
Physical Examination  
The investigator will perform physical examinations of all patients (see Appendix 1). 
Physical examinations 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 the neurologic system. Interval physical exams (symptom-directed) noting 
any changes from baseline will be recorded after the initial exam. 
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Physical exams will be performed at Screening, Day 1 of each treatment cycle, and on at the 
End of Treatment visit. Weight will be measured during Screening, Cycle 1 Day 1, Day 1 of 
each subsequent Odd treatment cycle, and at the End of Treatment visit. 
7.5 
Vital Signs  
Vital sign evaluations will include blood pressure, heart rate, respiratory rate, and 
temperature. Vital signs will be collected as indicated in Schedule of Events (Appendix 1).  
Vital signs will be performed at Screening. On the first dose of study treatment (Cycle 1, 
Day 1), vital signs will be taken at the following time points: 
• Prior to initiation of margetuximab or trastuzumab infusion  
• at end of margetuximab or trastuzumab infusion, and  
• at 60 minutes (± 10 minutes) after infusion with margetuximab or trastuzumab.  
For subsequent cycles, vital signs will be collected only at the start and end of margetuximab 
or trastuzumab infusion as indicated in Appendix 1. 
If a PK sample collection coincides with measurement of vital signs, the PK sample should 
be collected first and vital sign measurements taken after the patient has rested for 
approximately 5 - 10 minutes. The planned times of the vital sign assessments will be 
recorded on the eCRFs. 
7.6 
Clinical Laboratory Tests  
Local laboratories should be used for all clinical decision-making, including but not limited 
to, decisions regarding chemotherapy administration and dose adjustments, if needed. 
Necessary laboratory testing for patient safety should be performed as required by the 
clinical situation. Local laboratory testing will be used for confirmation of pregnancy status 
prior to dosing according to the protocol schedule.  
With Protocol Amendment 4, blood and urine samples for testing at a central laboratory will 
no longer be collected. Instead, blood and urine samples for safety will be collected 
according to institutional standard of care for patients who are receiving a HER2-targeted 
agent (margetuximab or trastuzumab). Local labs with units and normal ranges will be 
reported only as AEs, if clinically significant, or within Serious Adverse Event reporting. 
Clinically significant labs, in the Investigator’s opinion, mean a disease and/or organ toxicity 
that is new, has worsened from baseline, or requires additional active management.   
MacroGenics or its designee will provide the following blood sampling supplies for central 
lab ADA testing only: polypropylene transport tubes, labels, and shipping supplies. Serum 
tubes should be labeled with the Patient ID and date of sampling. The Investigator will 
maintain a log with the same data. 
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Specimens must be appropriately prepared, divided if appropriate, frozen, and shipped (while 
often retaining certain replicate samples at the site) according to the instructions in the 
Laboratory Manual. 
Please consult the Laboratory Manual for specific directions on the collection and processing 
of samples.  
7.7 
Samples for HER2 Testing  
A pathologic specimen or unstained slides are requested whenever possible for central HER2 
testing. There are two purposes for requesting samples. First, all patients will be requested to 
provide tissue samples for protocol-defined sensitivity analysis. Second, if a patient’s 
previous HER2 testing does not meet protocol requirements (i.e., not performed at an 
accredited reference laboratory), or if previous results are not available, a sample is required 
for central HER2 testing to determine study eligibility. Samples can be from the patient’s 
original biopsy or resection or be obtained from subsequent samples, but the most recently 
available specimen should be obtained. Samples can be from either primary or metastatic 
tissue. A testing report of a patient’s most recently available HER2+ specimen is acceptable 
to determine patient study eligibility provided the testing was performed at an accredited 
laboratory. Details of sample acquisition requirements are provided in the Laboratory 
Manual. 
7.8 
Cardiac Evaluations  
7.8.1 
12-Lead Electrocardiograms  
Analysis of electrocardiographic intervals and cardiac adverse events in this trial revealed no 
safety signal for margetuximab. With Protocol Amendment 4, ECGs will no longer be 
collected and analyzed centrally. Rather, ECGs should be collected and interpreted locally 
according to institutional standard of care. Findings will be reported only as AEs, if clinically 
significant in the view of the Investigator, or within Serious Adverse Event reporting. 
7.8.2 
Multigated Acquisition Ventriculography Scanning and 
Echocardiography  
MUGA scans or echocardiograms will be obtained and analyzed locally in all patients 
according to the Schedule of Events (Appendix 1). The same modality should be used 
throughout the study for any given patient. All MUGA scans or echocardiography performed 
will be evaluated for the change in LVEF from baseline.  
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7.9 
Adverse Events  
7.9.1 
Criteria for Evaluation  
• Safety assessment will be based on the evaluation of AEs from the time of 
initiation of any study therapy through the End of Treatment visit (or 28 days after 
the last dose of study drug, whichever occurs later) and will be determined based 
on signs, symptoms, physical examination findings and/or laboratory test results 
from enrolled patients as appropriate. Local labs with units and normal ranges 
will be reported only as AEs, if clinically significant, or within Serious Adverse 
Event reporting. Clinically significant labs, in the Investigator’s opinion, mean a 
disease and/or organ toxicity that is new, has worsened from baseline, or requires 
additional active management.   
• All AEs (related to the protocol or not) will be collected from the time the patient 
receives the first dose of any study medication. 
• AEs reported between the time the patient signed the informed consent and the 
administration of the first dose of any study medication will be captured as 
concurrent medical history unless due to a protocol-related procedure. 
• AE and SAE recording will continue until the End of Treatment visit is performed 
(or 28 days after the last dose of study drug, whichever is later). 
• 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 disease progression only, without any 
other SAE) will be documented as an anti-tumor activity outcome and not as an 
SAE. If an SAE occurs in a patient and it is unclear whether the event is related to 
progressive disease, the SAE should be reported 
7.9.2 
Definitions  
7.9.2.1 
Adverse Event  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
An AE will also be considered to be any untoward effect of a study-related procedure, 
conducted after signed informed consent and prior to study drug administration. 
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7.9.2.2 
Adverse Drug Reaction  
Adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. As used herein, the phrase “response to a medicinal product” means that 
a causal relationship between a medicinal product and an AE is at least a reasonable 
possibility (i.e., the relationship cannot be ruled out). 
7.9.2.3 
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 of such events could be appropriate. An AESI may be a 
serious or non-serious AE, which may require further investigation to fully characterize and 
understand it. 
7.9.2.4 
Treatment Emergent Adverse Event  
An event that is temporally associated with administration of study product is defined as a 
treatment emergent adverse event (TEAE). Events meeting this definition will be those 
occurring during or after administration of the first dose of study drug. Events that existed 
before the first administration of study drug and then increased in severity during or after the 
first administration of study product will also be considered treatment emergent. Such events 
will be captured on the eCRF as new events, with the onset date as the date of the increase in 
severity.  
7.9.2.5 
Product Quality Issue  
Product quality issues are defined as abnormalities that may be introduced during the 
manufacturing/labelling, packaging, shipping, handling or storage of the products. They may 
occur with or without clinical consequences.  
7.9.2.6 
Serious Adverse Events  
An SAE is any untoward medical occurrence that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization (even if the 
event is Grade 1) unless for an elective procedure unrelated to the study or 
underlying disease. 
• Persistent or significant disability or incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Congenital anomaly/birth defect 
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• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered SAEs when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization; or the development of 
drug dependency or drug abuse. 
7.9.2.7 
Immediately Reportable Event (IRE)  
IREs are events that must be reported immediately to MacroGenics Product Safety, or 
assigned designee, within 24 hours of being identified. IREs include but are not limited to:  
• 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 six 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. 
• AESI requiring immediate reporting include (see Section 7.9.3 below): 
o Grade 3 or greater infusion-related reactions or Cytokine Release 
Syndrome (see Section 6.6.1) 
o Left ventricular dysfunction leading to dose delay or discontinuation (see 
Section 7.8) 
• Administration of a dose significantly greater than the planned dose of any study 
agent (margetuximab, trastuzumab, or chemotherapy) resulting in an event of 
clinical consequence. 
• Any suspected transmission of an infectious agent via study drug (margetuximab 
or trastuzumab) 
• Withdrawal of the patient from study drug (margetuximab or trastuzumab) 
administration for any reason, including AE, other than disease progression. 
• Any abnormal liver enzyme laboratory value meeting criteria for potential Hy’s 
Law, defined as AST and ALT values of ≥ 3.0 × ULN with total bilirubin level of 
≥ 2.0 × ULN without an alternate etiology for the abnormal values. 
• Product Quality Issue with clinical consequences. 
In those cases, in which the IRE is considered related to study drug and the event of 
sufficient clinical concern to warrant study drug discontinuation, the study drug may be 
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discontinued and the patient will continue participation in the study for observational safety 
and analysis (except for cases where the patient is withdrawn from the study by the 
investigator). At any time after completion of the study, if an investigator becomes aware of 
an SAE that is suspected related to study drug, the investigator should report the event to 
MacroGenics Product Safety immediately. 
A physician’s assessment of the event is expected to be completed in conjunction with 
reporting an IRE to MacroGenics Product Safety. 
7.9.3 
Adverse Events of Special Interest  
AESI will include the following: 
• All infusion-related reactions; only Grade 3 or greater will be reported as 
Immediate Reportable Events.  
• Left ventricular dysfunction requiring delay or cessation of margetuximab or 
trastuzumab administration 
7.9.4 
Product Quality Issue with Clinical Consequences  
If a product quality issue results in an event of clinical consequences, from the use of study 
product, it must be immediately reported to the sponsor/designee as an IRE. The sponsor will 
collect the information and evaluate accordingly to protect the safety of the study patients. 
7.9.5 
Performing Adverse Event Assessments  
Medical evaluation and classification of the AE must be performed by the investigator who is 
qualified to review AE information. The determination of seriousness, severity, and causality 
must be made according to the criteria described below.  
7.9.5.1 
Assessment of Seriousness  
Event seriousness will be determined according to the definition of an SAE in 
Section 7.9.2.6. Seriousness serves as a guide for defining regulatory reporting obligations 
for AEs. 
7.9.5.2 
Assessment of Severity  
Event severity will be assigned according to the Investigator’s assessment using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 (for described events and 
syndromes). For events not contained in CTCAE, the investigator may assign severity 
according to the following scale: 
• Grade 1= Mild 
• Grade 2 = Moderate AE 
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• Grade 3 = Severe AE 
• Grade 4 = Life-threatening or disabling AE 
• Grade 5 = Death related to AE 
Any event or laboratory value judged as Grade 4 severity should be separately evaluated to 
determine whether it also meets the SAE criterion of “immediately life threatening.” (See 
Section 7.9.2.6). 
Note: Severity is not synonymous with seriousness. The term “severe” is often used to 
describe the intensity (severity) of a specific event. The event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient's life or functioning. 
7.9.5.3 
Assessment of Causality  
The Investigator is required to provide an assessment of causality or relationship of AEs to 
the study drug (margetuximab or trastuzumab) based on 1) temporal relationship of the event 
to the administration of study drug, 2) whether an alternative etiology has been identified, 
and 3) biological plausibility. If, in investigator’s opinion the event is not related to the study 
drug but to the chemotherapy used in combination with margetuximab or trastuzumab, the 
investigator is also required to make causality relationship with the chemotherapy based on 
the product label for that specific country/region. The causality assessment categories that 
will be used for this study are described below. 
Causality assessments that are considered not related to study drug:  
None: 
The event is related to an etiology other than the study drug (the alternative 
etiology should be documented in the patient’s medical record). 
Unlikely: 
The event is unlikely to be related to the study drug and likely to be related to 
factors other than study drug. 
If an SAE is considered "unlikely" or "unrelated" to study drug, the Investigator should offer 
his/her clinical opinion as to what factor(s), agent(s), or process(es) were the likely causative 
mechanism for the event.  
Causality assessments that are considered related to study drug:  
Possible: 
There is an association between the event and the administration of the study 
drug and there is a plausible mechanism for the event to be related to study 
drug; but there may also be alternative etiology, such as characteristics of the 
patient’s clinical status or underlying disease. 
Probable: 
There is an association between the event and the administration of study 
drug, a plausible mechanism for the event to be related to the study drug and 
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the event could not be reasonably explained by known characteristics of the 
patient’s clinical status or an alternative etiology is not apparent. 
Definite: 
There is an association between the event and the administration of study 
drug; a plausible mechanism for the event to be related to the study drug and 
causes other than the study drug has been ruled out and/or the event re-
appeared on re-exposure to the study drug. 
7.9.5.4 
Assessment of Expectedness  
As part of the regulatory reporting requirements, the Sponsor must perform an assessment of 
expectedness (expected/unexpected from the perspective of previously observed, not on the 
basis of what might be anticipated from the pharmacological properties of a medicinal 
product) for AEs. AEs will be considered unexpected if the nature, seriousness, severity or 
outcome of the reaction(s) is not consistent with the reference information (e.g., the Adverse 
Drug Reaction section of the Investigator’s Brochure) for the study product.  
7.9.6 
Reporting of Adverse Events to the Sponsor  
Throughout the study, the investigator must document all AEs and SAEs on the eCRF in a 
timely manner. AEs will be collected and followed from the time the patient provides 
informed consent for the study until the End of Treatment visit or 28 days after the last dose 
of study drug, whichever occurs later. If a patient experiences an AE after the informed 
consent document is signed and prior to treatment with study drug, it should be captured as 
medical history; however, if the investigator believes the AE may have been caused by a 
protocol-related procedure it will be recorded as a protocol-related AE and entered onto the 
eCRF. 
To identify the occurrence of any new medical complaints or worsening of previous 
complaints, non-leading questioning should be posed to the patient. 
Events related to disease progression/worsening of underlying disease (including those with a 
fatal outcome) will be collected as efficacy endpoints, and not documented as AEs/SAEs. 
These events may not qualify for expedited reporting to regulatory agencies if consistent with 
expected rates of progression for the underlying disease. However, if an SAE occurs in a 
patient and it is unclear if the event is due to progressive disease, the SAE should be 
reported. 
If a patient reports signs and symptoms that represent a single medical syndrome, diagnosis, 
or concept, the syndrome/diagnosis/concept should be documented (e.g., cough, runny nose, 
fever = upper respiratory tract infection) in the eCRF. 
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.  
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7.9.6.1 
Changes in Clinical Laboratory Parameters  
Safety laboratory assessments, whether performed locally at the discretion of the investigator 
or as the result of central testing will be evaluated by the Investigator to ensure patient safety. 
The Investigator is responsible for reviewing the results of all laboratory tests as they become 
available. Clinically important discrepancies between local and central testing results should 
be addressed as appropriate. Laboratory tests will be graded according to CTCAE v 4.03.  
Laboratory values that fall outside of a clinically accepted reference range or values that 
differ significantly from previous values must be evaluated by the investigator for clinical 
significance. The investigator may repeat the laboratory test or request additional tests to 
verify the results of the original laboratory tests. If the Investigator determines the laboratory 
value is an abnormal change from baseline and is of clinical significance for that patient, it is 
considered an AE.  
Generally, Grade 1 laboratory findings need not be reported as AEs unless clinically 
significant. The Investigator will evaluate laboratory findings of ≥ Grade 2 or higher 
classification to determine their clinical significance and if an AE has occurred. Consistent 
with the CTCAE designation of Grade 3 events as severe or medically significant and 
Grade 4 events as life-threatening, Grade 3 and Grade 4 laboratory findings should be 
reported as AEs or SAEs, as appropriate. Grade 2 laboratory findings may be reported as AEs 
if, in the opinion of the Investigator, the event exhibits clinical significance. If clinically 
relevant abnormal laboratory values are associated with clinical symptom(s), or consistent 
with a diagnosis, the diagnosis should be reported as the AE (e.g., hemoglobin 9 g/dL in an 
adult female = anemia). If these clinically relevant abnormal laboratory values do not result 
in a diagnosis, the test result or finding should be reported as the AE assuming that it does 
not represent a laboratory error. Repeat testing may be indicated. Such laboratory values 
should generally be recorded as “increased” or “decreased” (e.g., change from baseline 
hemoglobin of 13 g/dL to 11g/dL= hemoglobin decreased). Investigators are required to 
report any abnormal liver enzyme laboratory values meeting the criteria for potential Hy’s 
Law as described in Section 7.9.2.7 for immediately reportable event.) 
7.9.7 
Notification to the Sponsor of Events Requiring Immediate 
Reporting  
IREs, as defined in Section 7.9.2, are events that must be reported immediately (within 
24 hours of identification) to MacroGenics Product Safety or MacroGenics designee 
responsible for Product Safety (e.g., contract research organization [CRO]) by completing the 
appropriate eCRF(s)/forms. Throughout the study, the Investigator must ensure 
documentation of all AEs in the eCRF in a timely manner 
In case of patient or patient partner pregnancy, the MacroGenics Pregnancy Exposure eCRF 
must also be completed per Study Procedures. The Investigator must attempt to follow the 
pregnancy to term or termination in order to report on outcome and health status of mother 
and child. 
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7.9.8 
Emergency Unblinding  
Not applicable. 
7.10 
Efficacy, Pharmacokinetic, Pharmacodynamic Assessments  
7.10.1 
Efficacy Assessments  
7.10.1.1 
Radiologic Evaluation  
Tumor assessments will be obtained at Screening using CT (with contrast) and/or MRI scans 
of the chest, abdomen and pelvis at time intervals as specified in Appendix 1 (Schedule of 
Events). Assessment of skin lesions identified at screening may be made by photography 
with a reference ruler or by caliper measurement as described in RECIST 1.1 and should be 
followed at regular intervals as for radiologic evaluation. Treatment will continue until 
disease progression, withdrawal from the study, or death. At each tumor assessment time 
point, radiologic assessment of tumor status will be made using RECIST 1.1 criteria. 
Investigators will assess tumor response(s) for determination of suitability for continued 
therapy and the secondary endpoint of Investigator Assessed PFS. All patients who have CR, 
PR, SD, or non-evaluable as their local radiological assessment are eligible for further 
therapy. Non-radiological evidence of disease progression should be clearly documented in 
the eCRF.  
With Protocol Amendment 4, central review of radiographic images is discontinued. 
Investigator-assessed PFS and ORR will continue to be measured according to the protocol 
schedule.   
All patients will have a bone scan performed at baseline and then as clinically indicated 
during the study for the assessment of bone metastasis. Patients with bone only disease 
should be followed at regular intervals by bone scan or CT or MRI scan at the same intervals 
as other patients. Patients with a history of treated brain metastasis who are otherwise eligible 
must have a baseline brain MRI or CT within 4 weeks prior to randomization and as 
clinically indicated thereafter. 
Tumor evaluations will be performed at baseline (prior to treatment) and every 2 cycles for 
the first 24 weeks of treatment; thereafter, beginning with Cycle 9, tumor evaluations will be 
performed every 4 cycles while on treatment or every 3 months during post-treatment follow-
up until documented progression, initiation of alternative anti-cancer therapy, lost to follow 
up, withdrawal of informed consent, death, or end of study. For patients who receive 
alternative anti-cancer therapy in absence of progression and have a new tumor assessment 
schedule for that anti-cancer therapy, every effort should be made to collect the date of the 
documented progression per that new tumor assessment schedule. 
It is recommended that any accumulation of fluid (pleural or pericardial effusion and/or 
ascites) that is new or increased in size from baseline, and, when appropriate, any new 
lesions noted by radiography, be assessed by cytology or histology to document progression. 
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Progression can only be documented from new or increasing fluid collections if cytology 
confirms that the fluid is malignant.  
7.10.1.2 
Digital Imaging of Skin Lesions  
When applicable, digital images of skin lesions will be obtained on the same schedule for 
radiographic evaluations.  
7.10.1.3 
Overall Survival  
Patients who are discontinued from study treatment will be followed up for their survival 
status at 3-month intervals (± one week) until withdrawal of informed consent, loss to follow 
up, or the end of study is reached. Procedures for patients lost to follow-up are described in 
Section 5.4.2.  
7.10.2 
Immunogenicity  
Immunogenicity evaluations will be performed only as indicated in the Schedule of Events 
(Appendix 1) for patients receiving margetuximab only. With Protocol Amendment 4, 
collection of samples for anti-drug antibody (ADA) assay will be decreased in frequency 
from once every 6 weeks (i.e., every 2 treatment cycles) to once every 12 weeks (i.e., every 4 
treatment cycles), consistent with radiographic evaluation. ADA samples will continue to be 
collected at end of treatment and during follow-up.  
The generation of ADA directed against margetuximab will be assayed using enzyme-linked 
immunosorbent assay (ELISA). The proportion of patients who are negative for ADA at 
baseline and become positive in this assay will be reported, as will 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. Samples with 
positive ADA will be evaluated for neutralizing activity. Immunogenicity samples from all 
patients may be retained for future evaluations of neutralizing antibodies as allowed per local 
requirements/regulations. 
Blood samples will be collected from the arm contralateral to the site of IV infusion. If an 
indwelling catheter is used, the fluid in the catheter will be removed and discarded prior to 
the collection of blood sample for ADA assessment. 
Procedures for the acquisition, handling and processing of ADA specimens are provided in 
the Laboratory Manual.  
7.10.3 
Pharmacokinetics  
With Protocol Amendment 4, PK sample collection will be discontinued for patients who are 
still receiving study treatment.   
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7.10.4 
Biomarkers  
Specimens will be collected for the determination of Fc receptor genotype (CD16A, CD32A, 
and CD32B), as allowable per local requirements. Procedures for the acquisition, handling 
and processing of biomarker specimens are provided in the Laboratory Manual.  
7.11 
Health-Related Quality of Life  
HRQoL will be evaluated using the EQ-5D-5L and NFBSI-16 (10, 16). The NFBSI-16 is a 
new measure based on the Functional Assessment of Cancer Therapy-Breast Cancer 
Symptom Index, with emphasis on patient-reported input regarding high-priority breast 
cancer–related symptoms (Appendix 5). The primary focus for analysis of NFBSI-16 
HRQoL scale will be on the FBSI-16 score. EQ-5D-5L (Appendix 6) and NFBSI-16 data 
will be collected at baseline (prior to therapy administration on Cycle 1 Day 1), Day 1 of 
each Odd cycle thereafter, and at the End of Treatment visit. Patients participating in the 
infusion sub-study are exempt from completing the HRQoL assessments. 
HRQoL data collection will continue until notification of discontinuation by the study 
Sponsor.  
7.12 
Sample Retention and Further Testing  
Samples acquired for protocol specified assays retained for study purposes 
(analysis/re-analysis) may be retained up to 2 years after last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are 
no pending or contemplated marketing applications in an ICH region or until at least 2 years 
have elapsed since formal discontinuation of clinical development of the investigational 
product. If allowed per local regulation/requirements, and patients consent to the use of their 
PK, ADA, and HER2 study samples for non-study research purposes, these samples may also 
be used for future research use (including assay development/optimization) and may be 
retained up to 15 years from the date of last patient enrolled. The DNA samples used for Fc 
Gamma receptor genotyping may be retained up to two years from the last patient enrolled.  
7.13 
Appropriateness of Measurements  
Routine laboratory evaluations including hematology, chemistry, special chemistry, 
coagulation, and urinalysis will be performed in a central laboratory. Central laboratory 
testing should be used to determine patient eligibility and assess overall safety in the study, 
unless the medical monitor approves the use of a local laboratory in place of an unanalyzable 
central laboratory sample. 
Local safety laboratory assessments will be used to make treatment-related decisions. 
Serum concentrations of margetuximab will be monitored using an ELISA-based sandwich 
assay. Standard bridging ELISAs will be carried out in the Sponsor’s designated central 
laboratory to characterize the immunogenicity of margetuximab. Analysis of PK data will be 
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carried out using industry standard software. Population PK modeling will be performed and 
an appropriate model and model parameters will be described.  
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8 
STUDY ACTIVITIES  
A table of study activities including Screening, On-Study, and End of Treatment visits is 
presented in Appendix 1, Schedule of Events. 
8.1 
Screening Period  
At the Screening visit, patients will enter the study upon signing the informed consent 
document. No screening activities outside of usual standard-of-care should be performed 
prior to obtaining informed consent from the patient. During the screening period, the 
Principal Investigator (PI) should review inclusion/exclusion criteria and verify that all 
assessments were performed within the protocol-specified windows and the patient is still 
eligible for the study. Only those patients who meet all inclusion/exclusion criteria specified 
in Section 5.1 and Section 5.2 will be entered into this study.  
8.1.1 
Up to 4 Weeks Prior to Randomization  
The following evaluations are to be performed within 28 days (4 weeks) prior to 
randomization in this study. 
• Perform radiographic tumor evaluations (Section 7.10.1.1) and digital imaging of 
skin lesions Section 7.10.1.2: 
o CT (with contrast) or MRI of chest, abdomen, and pelvis – all patients 
o Bone scan – all patients 
o CT or MRI of brain – patients with known, treated brain metastases or 
symptoms of brain metastases 
o Digital images of skin lesions – all applicable patients. 
 
The above tumor assessments will be considered baseline (Section 7.10.1.1). Tumor 
assessments performed as standard of care prior to study registration may be considered 
baseline and need not be repeated if completed within 4 weeks prior to randomization.  
• Perform MUGA scan or echocardiogram determination of LVEF (Section 7.8.2). 
A previous evaluation may be considered baseline if completed within 4 weeks 
prior to randomization. 
• Request archival pathological material from primary or metastatic site for central 
HER2 testing (formalin-fixed paraffin embedded [FPPE] tissue block or 
5 unstained slides). The most recent tumor biopsy from the patient should be 
obtained when available. If previous HER2 testing was performed at a reference 
laboratory and meets ASCO/CAP guidelines, the biopsy specimen is required only 
for efficacy sensitivity analyses, and the results are not required prior to 
randomization. If HER2 test results are not available from previous testing, this 
specimen may be used for eligibility purposes.  
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Procedures for the acquisition, handling and processing of specimens for central 
HER2 testing are provided in the Laboratory Manual.  
• Obtain documentation of HER2 status from most recent result available. 
• Perform toxicity review and AE assessment (with grading based on CTCAE, 
Version 4.03) (Section 7.9), and concomitant medications (Section 7.3). 
 
8.1.2 
Up to Two Weeks Prior to Randomization  
The following evaluations are to be performed within 14 days (2 weeks) prior to 
randomization. Results of central laboratory and ECG evaluations must be reviewed and 
patient eligibility confirmed prior to randomization to study drug.  
• Conduct medical history (Section 7.2). 
• Conduct physical examination (PE), including height and weight (Section 7.4). 
• Take vital signs (Section 7.5). 
• Evaluate ECOG performance status (Appendix 4). 
• Obtain ECG, standard 12-lead (in triplicate) (Section 7.8.1). 
• Obtain specimen for complete blood count (CBC) with differential and platelet 
count. 
• Obtain specimen for chemistry panel. 
• Perform serum -hCG pregnancy test for women of childbearing potential.  
• Perform toxicity review and AE assessment (with grading based on CTCAE, 
Version 4.03) (Section 7.9), and concomitant medications (Section 7.3). 
 
8.2 
Registration and Randomization  
Each patient must be randomized through an IxRS and dosed within 72 hours of 
randomization, with dosing preferably on the same day as randomization. Prior to 
randomization, the PI should review inclusion/exclusion criteria and verify that all screening 
assessments were performed within the protocol-specified screening windows and the patient 
is still eligible for the study. The date that informed consent is given is the first day of 
Screening.  
The following information should be provided during registration: 
• Patient Identification (ID) Number 
• Date of signed informed consent 
• Number of lines of therapy in the metastatic setting (≤2, >2) 
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• Number of metastatic sites (≤ 2, > 2) 
• Choice of backbone chemotherapy (capecitabine, eribulin, gemcitabine, or 
vinorelbine). 
8.2.1 
Registration for the Infusion Sub-Study  
• Patient Identification (ID) Number 
• Date of signed informed consent. 
8.3 
Cycle 1  
8.3.1 
Cycle 1 Day 1  
8.3.1.1 
Prior to First Dose of Study Treatment on Cycle 1 Day 1  
For some assessments, if the corresponding screening assessment was performed within the 
specified number of days prior to initiating study treatment on Cycle 1 Day1, the assessment 
need not be repeated prior to dosing on Cycle 1 Day 1. When this is the case, details are 
provided below.  
• Clinical assessments: 
o Review medical history (Section 7.2) 
o Conduct PE, including weight (Section 7.4) 
o Administer the NFBSI-16 and EQ-5D-5L questionnaire (Section 7.11; not 
required for infusion sub-study) 
o Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3). 
• Laboratory assessments for local laboratory testing: 
o Perform local urine or serum pregnancy test for women of childbearing 
potential. Pregnancy test must be negative to administer chemotherapy or 
study drug. 
o Local chemistry and hematology should be performed prior to dosing for 
all cycles as needed if the results of central testing are not yet available. 
• Laboratory assessments for central laboratory testing: 
o Obtain specimen for CBC with differential and platelet count  
 Not required if the Screening CBC with differential and platelet 
count (Section 8.1.2) was performed within 3 days of dosing with 
study treatment 
o Obtain specimen for chemistry panel  
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o Not required if the Screening chemistry panel (Section 8.1.2) was 
performed within 3 days of dosing with study treatment  
o Obtain specimen for PT, aPTT  
o Obtain specimen for urinalysis  
o Obtain specimen for PK sampling (margetuximab arm only, Section 
7.10.3) 
o Obtain specimen for FcγR genotyping – specimen must be obtained at the 
Cycle 1 Day 1 visit 
o Obtain specimen for ADA (margetuximab arm only, Section 7.10.2).  
 
8.3.1.2 
During and Following Administration of Study Treatment  
The following evaluations should be performed only after ALL pre-treatment evaluations 
described in Section 8.3.1.1 have been completed:  
• Administer chosen chemotherapy – per specific chemotherapy regimen (see 
Table 4) according to institutional guidelines, including guidelines for 
premedications. 
• Prior to initiation of margetuximab or trastuzumab infusion:  
o Obtain ECG (standard 12-lead in triplicate, Section 7.8.1)  
o Take vital signs (Section 7.5) 
• Administer margetuximab or trastuzumab (Section 6.3) 
• Following completion of margetuximab or trastuzumab infusion:  
o Obtain specimen for PK sampling (margetuximab arm only, 
Section 7.10.3)  
o Obtain ECG (standard 12-lead in triplicate, Section 7.8.1)  
o Take vital signs (Section 7.5): 
 At end of margetuximab or trastuzumab infusion, 
 At 60 minutes after end of margetuximab or trastuzumab infusion. 
 
8.3.2 
Cycle 1 Day 8  
If the patient is required to return to the study site on Cycle 1 Day 8 for chemotherapy 
administration, a toxicity review and AE assessment (Section 7.9), and review of 
concomitant medications (Section 7.3) should also be performed. Local laboratory 
evaluations should be performed as needed according to local practice and institutional 
guidelines.  
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8.4 
Study Evaluations for Even Cycles (e.g., Cycles 2, 4, 6, 8)  
Procedures required each visit during Even treatment cycles are described below (see also 
Schedule of Events in Appendix 1). All procedures should be performed on the scheduled 
study day with exception of MUGA/ECHO/radiology assessments, which may be performed 
within 14 days pre-dose (chemotherapy and study drug), unless otherwise specified. Day 8 
procedures are to be performed only if patients are required to return to the study site for 
chemotherapy administration. 
8.4.1 
Even Cycle Treatment Visits: Day 1  
8.4.1.1 
Prior to Administration of Study Treatments  
• Clinical assessments: 
o Conduct PE (Section 7.4)  
o Take vital signs (Section 7.5)  
o Obtain ECG according to institutional standard of care, as clinically 
indicated  
o Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3).  
• Laboratory assessments for local laboratory testing  
o Perform serum or urine pregnancy test for women of childbearing 
potential. Pregnancy test must be negative to administer chemotherapy or 
study drug. 
o Chemistry and/or hematology test(s) should be performed locally 
according to institutional standard of care prior to dosing for all cycles as 
needed.  
8.4.1.2 
Administration of Study Treatments  
• Administer chosen chemotherapy – per specific chemotherapy regimen (see 
Table 4) 
• Administer margetuximab or trastuzumab. 
8.4.1.3 
Following Administration of Study Treatments  
• Laboratory assessments for central laboratory testing  
o Obtain specimen for PK sampling (margetuximab arm only, 
Section 7.10.3)  
 Cycles 2 – 6 only 
• Clinical assessments: 
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o Take vital signs (Section 7.5)  
o Obtain ECG according to institutional standard of care as clinically 
indicated.  
8.4.2 
Even Cycle Treatment Visits: Day 8 (as needed)  
• Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3)  
• Administer chosen chemotherapy – per specific chemotherapy regimen (see 
Table 4).  
 
8.5 
Study Evaluations for Odd Cycles >1 (e.g., Cycles 3, 5, 7)  
Procedures required each visit during Odd treatment cycles are described below (see also 
Schedule of Event in Appendix 1). All procedures should be performed on the scheduled 
study day with exception of central laboratory assessments, which may be performed within 
3 days pre-dose (chemotherapy and study drug) and MUGA/ECHO/radiology assessments, 
which may be performed within 14 days pre-dose (chemotherapy and study drug), unless 
otherwise specified. Day 8 procedures are to be performed only if patients are required to 
return to the study site for chemotherapy administration.  
8.5.1 
Odd Cycle Treatment Visits: Day 1  
8.5.1.1 
Prior to Administration of Study Treatments  
• Clinical assessments: 
o Conduct PE, including weight (Section 7.4)  
o Take vital signs (Section 7.5) 
o Obtain ECG according to institutional standard of care as clinically 
indicated  
o Obtain MUGA scan or echocardiogram for determination of LVEF 
(Section 7.8.2) – within 7 days prior to Day 1 visit: Cycle 3, Cycle 5, and 
every 4th cycle thereafter (e.g., Cycles 9, 13, 17) while on treatment  
o Administer the NFBSI-16 and EQ-5D-5L questionnaire (Section 7.11; not 
required for infusion sub-study)  
o Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3). 
• Laboratory assessments for local laboratory testing  
o Perform serum or urine pregnancy test for women of childbearing 
potential. Pregnancy test must be negative to administer chemotherapy or 
study drug. 
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o Chemistry and/or hematology test(s) should be performed locally per 
institutional standard of care prior to dosing for all cycles as needed. 
o Obtain specimen for ADA (margetuximab arm only, Section 7.10.2)  
• Radiographic tumor evaluations and digital imaging of skin lesions – within 14 
days prior to Day 1 visit: 
o Obtain CT and/or MRI scan(s) (Section 7.10.1.1) 
o Obtain digital images of skin lesions (if applicable, Section 7.10.1.2). 
 
8.5.1.2 
Administration of Study Treatments  
• Administer chosen chemotherapy – per specific chemotherapy regimen (see 
Table 4) 
• Administer margetuximab or trastuzumab. 
 
8.5.1.3 
Following Administration of Study Treatments  
• Clinical assessments: 
o Take vital signs (Section 7.5) 
o Obtain ECG according to institutional standard of care as clinically 
indicated  
o Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3).  
 
8.5.2 
Odd Cycle Treatment Visits: Day 8 (as needed)  
• Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3)  
• Administer chosen chemotherapy-per specific chemotherapy regimen (see 
Table 4). 
8.6 
End of Treatment Visit  
Criteria for triggering the End of Treatment visit are specified in Section 4.1.5. The End of 
Treatment visit should be performed after the patient has met off-treatment criteria or has 
been followed for up to 28 days after the last dose of study drug. Procedures required for the 
End of Treatment Visit include the following (see also Schedule of Events in Appendix 1): 
• Clinical assessments: 
o Conduct PE, including weight (Section 7.4)  
o Take vital signs (Section 7.5)  
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o Evaluate ECOG performance status (Appendix 4) 
o Obtain MUGA scan or echocardiogram for determination of LVEF 
(Section 7.8.2) 
o Administer the NFBSI-16 and EQ-5D-5L questionnaire (Section 7.11; not 
required for infusion sub-study).   
o Perform toxicity review and AE assessment (Section 7.9), and review 
concomitant medications (Section 7.3).  
• Laboratory assessments: 
o Perform serum or urine pregnancy test locally for women of childbearing 
potential.  
o Obtain specimen for ADA (margetuximab arm only, Section 7.10.2).  
Safety Follow-up: Ongoing AEs at the time of study drug discontinuation will be followed to 
the End of Treatment visit or 28 days after the last dose of study drug, whichever occurs later. 
SAEs will be followed to resolution (see Section 7.9.2.6). 
8.7 
Post-Treatment Follow-up and Observation of Survival  
Follow-up information regarding disease and vital status (including dates of progression and 
death [including appropriate documentation such as a death certificate, if allowed by local 
regulations]), and additional cancer treatment(s) received will be requested by the Sponsor at 
3-month intervals (± 1 week) after treatment discontinuation until death, withdrawal of 
consent, lost to follow-up, or the end of study (Appendix 1). Procedures for patients lost to 
follow-up are described in Section 5.4.2. 
For patients discontinued from the study treatment for any reason other than disease 
progression, initiation of alternative anti-cancer therapy, lost to follow-up, withdrawal of 
informed consent, or death, radiologic tumor evaluations (Section 7.10.1.1) and digital 
imaging of skin lesions (if applicable, Section 7.10.1.2), should be performed every 3 months 
until one of the aforementioned criteria to stop tumor assessments is met.  
With Protocol Amendment 4, blood samples for immunogenicity will be obtained 3 months 
and 6 months after the  last dose of margetuximab. Details for acquisition, handling, and 
shipping of the specimens will be provided in the Laboratory Manual. 
Belgium only: monthly urine or serum pregnancy tests should be performed locally in women 
of childbearing potential for 7 months during the post-treatment follow-up period.  
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9 
PLANNED STATISTICAL METHODS  
9.1 
General Considerations  
All statistical inferences will be based on two-sided tests with an α-level of 0.05 unless 
otherwise noted. 
Categorical data will be summarized by the number and percent of patients falling within 
each category. Continuous variables will be summarized by descriptive statistics, including 
mean, standard deviation (SD), median, 25th, and 75th quartile. Time-to-event endpoints will 
be summarized by median durations, hazard ratios, and corresponding 95% confidence 
intervals (CIs). 
Unless otherwise noted, baseline values will be defined as the most recent value collected 
prior to the first dose of study drug.  
Data summaries and tabulations will be conducted using SAS software Version 9.2 or higher. 
A detailed analysis plan (SAP) will be prepared and submitted to regulatory health 
authorities, as per local requirements, before study initiation. 
9.2 
Independent Data Safety Monitoring Committee  
An independent Data Safety Monitoring Committee (DSMC) will oversee the ongoing 
monitoring and interpretation of the safety and efficacy data from this study. A DSMC charter 
will be created, reviewed, and approved by the committee prior to study initiation. The 
independent DSMC will review safety data, with the first assessment to occur approximately 
90 days after enrollment of the first patient, the second assessment to occur 30 days after 
enrollment of the 30th patient and the third assessment to occur 30 days after enrollment of 
the 60th patient, or 90 days after the second DSMC assessment (i.e., following enrollment of 
the 30th patient), whichever is later. If no adverse safety signal is identified, the DSMC will 
meet on a bi-annual basis thereafter. If, according to this schedule, a DSMC meeting is 
expected to occur near the time of a planned interim analysis (see Section 9.9.1), the timing 
of the DSMC meeting will be adjusted to align with the interim analysis. More frequent 
assessments may be used if emergent safety data warrant. The DSMC will evaluate aggregate 
safety data comparing the two arms and also evaluate safety within each baseline 
chemotherapy to ensure patient safety. For these reviews, the committee will be provided 
with safety tables and data listings. When approximately 100 PFS events have occurred, the 
DSMC will be asked to make a recommendation regarding continuation of full enrollment to 
the study or early termination of the study for either safety or futility reasons. The DSMC 
will be empowered to recommend changes to the study, including discontinuation or 
modification of an arm or overall discontinuation of the study as appropriate. 
The DSMC meetings will be based on enrollment to the randomized cohorts only. 
Sub-study patient safety monitoring will be conducted by the MacroGenics Product Safety 
group.  
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After the final DSMC meeting to oversee final protocol-specified OS analysis, MacroGenics 
Product Safety will oversee all study patient safety monitoring. 
9.3 
Determination of Sample Size  
There are 2 primary endpoints in this study. The first primary endpoint is centrally 
determined PFS and the second primary endpoint is OS. These two endpoints will be 
assessed in a hierarchical manner with PFS being assessed first. OS will only be assessed if a 
statistically significant difference is obtained in PFS. 
It is estimated that the median PFS for patients treated with trastuzumab and chemotherapy is 
4 months. To detect a 2-month improvement in median PFS from 4 months to 6 months 
(hazard ratio [HR]=0.67) in patients treated with margetuximab plus chemotherapy, a total of 
257 PFS events are required to provide 90% power at a 2-sided alpha=0.05. The analysis of 
the primary PFS endpoint will occur when about 257 events have occurred or when all 
patients have been randomized, whichever occurs later. 
The sample size is calculated to ensure 80% power for the analysis of OS. The median OS 
for patients treated with trastuzumab plus chemotherapy is estimated to be 12 months. This 
study is designed to detect an increase to a median OS of 16 months in patients treated with 
margetuximab plus chemotherapy (HR=0.75). Assuming that OS is exponentially distributed 
with median OS time of 12 months for the trastuzumab plus chemotherapy arm and 
16 months for the margetuximab plus chemotherapy arm, 2 interim analyses are performed 
as described in Section 9.9.1, and a Lan-DeMets alpha spending function using an 
O’Brien-Fleming stopping boundary is used, approximately 385 deaths will be required to 
provide 80% power to achieve statistical significance at overall type I error of 2-sided 
alpha=0.05. It is anticipated that about 530 patients will be accrued to achieve this number of 
events. Patients will be enrolled over 24 months, and estimated to remain on study for an 
average of 16 months, for a total anticipated study duration of approximately 40 months.  
The planned sample size for the infusion sub-study is approximately 78 patients, 
approximately 18 patients for Stage A and about 60 patients for Stage B. The sample size of 
60 patients for Stage B of the infusion sub-study is derived to provide adequate assessment of 
primary safety endpoint for the sub-study.   
The overall total number of patients enrolled for the entire study is expected to be 
approximately 608. 
9.3.1 
Analysis Populations  
Three analysis populations are defined: 
• Intent-to-Treat Population – all patients randomized. Patients will be analyzed 
according to the treatment (margetuximab or trastuzumab) assigned during 
randomization. This population will be used to summarize baseline data and 
evaluate PFS, OS, and HRQoL.  
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• Response Evaluable Population — all patients who are randomized who have 
measurable disease at baseline. This population will be used to evaluate ORR and 
CBR. 
• Safety Population – all patients who are randomized and receive any amount of 
any study treatment. Patients will be analyzed according to the actual treatment 
received rather than the treatment group to which they were randomized. This 
population will be used for safety, PK, PD, and immunogenicity analyses. 
 
9.4 
Demographics and Baseline Characteristics  
Patient disposition, demographics, baseline characteristics, disease history, medical history, 
concomitant medications, and study drug exposure data will be summarized using descriptive 
statistics. 
9.5 
Safety Endpoint(s) and Analyses  
9.5.1 
Adverse Events  
AEs will be coded to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
Only treatment-emergent AEs, as defined in Section 7.9.2, will be summarized in tables. 
Events prior to treatment (e.g., due to study-related procedure) will be listed in an appendix 
to the final study report.  
The following tables of AE data will be created to summarize the number and percent of 
patients who experience at least one event of each of the following types: 
• All AEs by CTCAE grade 
• Drug-related AEs by CTCAE grade by onset of cycle (as a separate table) 
• All SAEs (this may be a listing if there are few events) 
• Drug-related SAEs by onset of cycle (as a separate table) 
• Fatal AEs (this may be a listing if there are few events) 
• AEs that result in study drug discontinuation 
• AESI by onset of cycle (as a separate table) 
• AEs which lead to dose interruption by onset of cycle (as a separate table) 
• AEs that lead to withdrawal of study drug by onset of cycle (as a separate table) 
 
All of these tables will display the number and percent of patients that experience the given 
event and will display events by System Organ Class (SOC) and preferred term. Events will 
be displayed alphabetically for SOC and in descending order of overall preferred term 
incidence within each SOC. 
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An overall summary of AEs will display the number and percent of patients who experience 
at least one event of each of the following types: 
• Any AE  
• Any drug-related AE 
• Any AE Grade 3 
• Any drug-related AE Grade 3 
• Any SAE 
• Any drug-related SAEs 
• AEs which lead to dose interruption 
• Any AE that results in study drug discontinuation 
• Any AEs that result in withdrawal from study drug  
• Any fatal AE 
• Any AESIs 
 
9.5.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified 
labs. Summaries will be grouped by laboratory panel (e.g., hematology, blood chemistry, and 
urinalysis) and will be displayed by visit for each laboratory parameter. 
In cases where an abnormality resulted in a repeat laboratory test, the repeat value will be 
used for the summaries. A list of repeated laboratories including original values and repeat 
values will be included.  
Graphs of mean values over time may also be generated. 
9.5.3 
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. LVEF will be evaluated by echocardiogram or MUGA 
and changes from baseline summarized.  
With Protocol Amendment 4, ECGs will no longer be collected and analyzed centrally. 
Instead, ECGs will be collected and interpreted locally according to institutional standard of 
care.  
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9.6 
Efficacy Endpoints and Analyses  
Progression-free survival – defined as the time from randomization date to the date of first 
documented disease progression or death from any cause, whichever occurs first. For patients 
who are not known to be dead or progressed at time of data cut-off for PFS analysis, the PFS 
will be censored at the last tumor assessment.    
Incomplete or missing data can complicate interpretation of PFS. Appendix 3 describes the 
handling of these data for the PFS analysis. 
Overall survival – defined as the time from randomization 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. 
Objective response rate – the proportion of patients in the response evaluable population 
achieving a best response of CR or PR when such responses are confirmed at least 28 days 
after initial observation of response. Patients who have baseline measurable disease but no 
post-baseline radiographic assessment will be considered as non-responders. 
Duration of response – defined as the time from initial response to date of first documented 
disease progression or death from any cause, whichever occurs first. DoR will be analyzed 
for responding patients only. For responding patients who are not known to be dead or 
progressed at the time of data cut-off for DoR analysis, the DoR will be censored at the last 
tumor assessment. 
Clinical benefit rate – the proportion of patients in the response evaluable population 
achieving a best response of CR, PR, or SD of duration >6 months. 
HRQoL – Patients will be administered the EQ-5D-5L and NFBSI-16 quality of life 
questionnaires at baseline, Day 1 of each odd cycle, and at study completion. Change from 
baseline on global scores will be assessed. HRQoL data collection will continue until 
notification of discontinuation by the study Sponsor.  
9.6.1 
Primary Endpoints  
The primary analysis for PFS will be conducted when about 257 PFS events have occurred or 
when all patients have been randomized, whichever occurs later. OS will be conducted at the 
time of PFS analysis and subsequently when 70% of the OS events and a final OS analysis 
when about 385 survival events have occurred.   
For both PFS and OS, Kaplan-Meier methods will be used to generate survival curves and 
estimate the median OS and PFS along with corresponding 95% CIs for each treatment 
group. A log-rank test stratified by protocol defined stratification factors will be used to 
compare both time-to-event endpoints between the two treatment groups. In addition, hazard 
ratios and 95% CIs will be assessed using stratified Cox proportional hazards models with 
treatment as the only covariate. Sensitivity analyses of PFS and OS will be performed; 
further details are provided in the SAP. 
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The following are pre-defined stratification factors: 
• Number of metastatic sites (0-2, >2) 
• Number of lines of prior therapy in the metastatic setting (≤2, >2)  
• Choice of backbone chemotherapy (capecitabine, eribulin, gemcitabine, or 
vinorelbine) 
 
In addition, the hazard ratios and 95% CIs for PFS and OS in each subgroup of the above 
three stratification factors as well as the following subgroups will be assessed using 
unstratified Cox proportional hazards model with treatment as only covariate and presented 
by forest plots: 
• Prior use of T-DM1 (yes, no) 
• Region (North America, Europe, Other) 
• HER2 status (3+ or ISH amplified, Other) 
• Age (≤60 and >60 years) 
• Race (White, Black, Asian, Other) 
• ECOG (0 and 1) 
• ER and PR status (ER+ and/or PR+, ER- and PR-, Unknown) 
• CD16A haplotypes (FF, FV, or VV) 
• CD32A haplotypes (HH, HR, or RR) 
• CD32B haplotypes (II, IT, or TT) 
 
9.6.1.1 
Primary Endpoint for the Infusion Sub-Study  
The number of patients with Grade 3 or higher IRR by the end of Cycle 2 will be assessed 
using descriptive statistics.   
9.6.2 
Secondary Endpoints  
The secondary endpoints of investigator-assessed PFS and independent review-assessed ORR 
will be assessed using the Hochberg step-up procedure for multiplicity adjustment. P-values 
will be assessed in descending order. If the least significant p-value<0.05, then both 
hypotheses are rejected. Otherwise, this endpoint is retained and the second p-value is tested 
at p<0.025. If a p-value<0.025 (0.05/2) is obtained, this hypothesis is rejected. Otherwise, 
both hypotheses are retained.  
Investigator-assessed PFS will be analyzed using the same methods as described above for 
the primary endpoint of PFS. 
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Independent review-assessed ORR will be compared between groups using a 
Mantel-Haenszel statistic stratified by protocol defined stratification factors.  
9.6.2.1 
Secondary Endpoint for Infusion Sub-study  
The number of patients with any grade IRR will be assessed using descriptive statistics.   
9.6.3 
Tertiary Endpoints  
No multiplicity adjustment will be used for tertiary endpoints. 
Direct reports from patients will be obtained using the NFBSI-16 and EQ-5D-5L 
Questionnaires (10, 16). Responses Data will be collected at baseline, Day 1 of each Odd 
cycle, and at the End of Treatment visit. The primary patient-reported outcome (PRO) 
endpoint for analysis will be the NFBSI-16 total score, with secondary analysis of the 
subscales that add to the total (disease related symptoms, treatment side effects, and 
function/well-being. Analyses using mixed model repeated measures using the baseline score 
and protocol defined stratification factors are planned as covariates. Subscale scores will be 
tabulated and summarized. Data from the EQ-5D-5L scale will be summarized by study visit. 
To minimize missing data, sites will be instructed and patients educated on the importance of 
recording the direct patient experience in order to appreciate the positive and negative 
aspects of treating advanced breast cancer, and they will specifically be trained on best 
practices for patient enrollment, adherence to endpoint data collection requirements, and 
methods to ensure complete data capture and management. Every effort will be made to 
collect survey data at all defined visits including at early withdrawal. Reasons for missing 
data will be summarized. 
Duration of response, where response is assessed by study investigators and by independent 
review, respectively, will be analyzed using Kaplan-Meier methods and compared between 
two treatment groups using a stratified log-rank test. 
Investigator assessed ORR will also be compared between two treatment groups using a 
Mantel-Haenszel statistic stratified by protocol defined stratification factors. 
Clinical benefit rate, where response is assessed by study investigators and by independent 
review, respectively, will also be compared between two treatment groups using a Mantel-
Haenszel statistic stratified by protocol defined stratification factors. 
Change in tumor size over time will be summarized and the best percentage change from 
baseline will be presented by waterfall plots. Change calculations will be based on target 
lesions only. 
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9.6.4 
Exploratory Analyses  
The effects of margetuximab on PFS and OS as compared to trastuzumab in each allelic 
variation of CD16A, CD32A, and CD32B will be evaluated by the estimated hazard ratios 
and 95% CIs as described in the subgroup portion of Section 9.6.1.  
In addition, an exploratory analysis will be performed to evaluate the impact of subsequent 
use of T-DM1 on the effect of margetuximab on OS. The details will be provided in the SAP. 
9.7 
Pharmacokinetic and Exposure-Response Analyses  
Serum concentrations of margetuximab will be summarized by study visits using descriptive 
statistics and graphed over time. Any population PK modeling will be performed by an 
external vendor. An analysis plan will be created prior to analysis. 
Summary statistics will be tabulated for serum PK parameters by margetuximab dose. 
Geometric means and percent coefficients of variation will be reported for Cmax, AUCtau, 
AUCinf, and Ctrough; arithmetic means and standard deviations will be reported for Thalf, CL, 
and Vss; and medians, minimum, and maximum will be reported for Tmax.  
Exposure-response analyses will be conducted separately using key efficacy and safety 
parameters of interest. An analysis plan will be created prior to analysis. 
9.8 
Immunogenicity Analyses  
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 
patients who have positive ADA at baseline that increases or decreases in titer over the 
course of treatment will be summarized. Neutralizing activity will be determined for samples 
with positive ADA. The effects of ADA on key PK, efficacy, and safety parameters will be 
investigated. 
9.9 
Timing of Analyses  
Patients in the infusion sub-study are not included in the interim analysis of OS, futility, and 
final analysis. 
9.9.1 
Interim Analyses  
9.9.1.1 
Interim Analyses for OS  
Two interim analyses of OS will be conducted for the randomized population. The first will 
occur at the time of the primary PFS analysis, when approximately 257 PFS events have 
occurred, assuming all patients have been enrolled and had at least one post-baseline 
assessment or in the absence of a post-baseline tumor assessment, have experienced clearly 
documented clinical disease progression. The second interim analysis will occur when 70% 
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of the target of 385 OS events have occurred unless that threshold was met at the time of PFS 
analysis. 
The overall type 1 error rate is controlled at 2-sided 0.05 using the sequential analysis of PFS 
followed by OS if PFS is statistically significant and using the Lan-DeMets alpha spending 
function with O’Brien-Fleming boundaries for the OS analyses. The efficacy boundaries 
based on this method will depend on the actual observed number of OS events at each 
analysis and hence will be calculated and provided to DSMC once the actual number of OS 
events is known for each interim analysis. For example, if we observe 139 OS events (as 
expected per simulation) at the time of observing 257 PFS events for the primary PFS 
analysis, then the efficacy boundaries at each interim and final analysis are as follows 
(ADDPlan v6, with O’Brien-Fleming type alpha spending function and Schoenfeld formula 
for sample size calculation).    
Table 5 
Planned Interim Analyses  
Analysis 
Timing of Analysis 
Observed number (% of 
information fraction) of 
OS Events at Each 
Analysis 
Efficacy Boundary in 
Terms of Two-Sided 
Significance Level 
First Interim  
Time of Primary PFS Analysis 
139 (36%) 
0.0004 
Second Interim 
70% of Overall OS Events 
270 (70%) 
0.0146 
Final 
100% of Overall OS Events 
385 (100%) 
0.0454 
 
9.9.1.2 
Interim Futility Analysis for PFS  
When approximately 100 PFS events have occurred in the randomized population, a futility 
analysis will be conducted. The DSMC will be asked to make a recommendation to continue 
or terminate the study for either a safety or futility reason. Futility will be assessed using 
conditional power conducted both under the initial study design and under the current trend 
of the data.  
The DSMC will evaluate study conduct and patient safety as well as conditional power. The 
committee may recommend study termination if the conditional power is low (as guidance, it 
is considered low if the conditional power is less than 20%), if there are safety issues, or if 
under the current conduct of the study, study objectives are unlikely to be achieved.  
9.9.2 
Final Analysis  
The final analysis of PFS will take place when about 257 PFS events have occurred in the 
randomized population or when all patients have been randomized, whichever occurs later. 
The final OS analysis will take place when about 385 events have occurred. 
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10 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. 
MacroGenics, Inc., and/or its representatives will do the following: 
• Provide instructional material to the study sites, as appropriate. 
• Sponsor a start-up training session (Investigator Meeting or Study Initiation Visit) 
to instruct the Investigators and study coordinators. This session will give 
instruction on the protocol, the completion of the CRFs, 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 
e-mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer checks to detect and 
query errors in data collection. 
• Conduct a quality review of the database. 
 
10.1 
Monitoring, Auditing and Inspections  
To ensure the safety of participants in the study, compliance with applicable regulations, and 
ensure accurate, complete, and reliable data, the Investigator will keep records of laboratory 
tests, clinical notes, and patient medical records in the patient files as source documents for 
the study (refer to Section 11.6 for additional information on source documents). 
MacroGenics, Inc., or its designee will monitor the study on a regular basis throughout the 
study period according to the study monitoring plan. The Investigator will allocate adequate 
time for such monitoring activities. The study monitor periodically will conduct a 
cross-check of a sample of the patient data recorded on CRFs against source documents at 
the study site. The Investigator will also ensure that the monitor is given access to all the 
above noted study-related documents, source documents (regardless of media) and study-
related facilities (e.g., investigational pharmacy, etc.), and has adequate space to conduct the 
monitoring visit. Queries may be raised if any datum is unclear or contradictory. The 
Investigator and site personnel must address all queries in a timely manner. 
Participation as an Investigator in this study implies acceptance of the potential for inspection 
by the study Sponsor/Representatives, US or non-US government regulatory authorities, 
IRB/IEC and applicable compliance and quality assurance offices. The Investigator will 
permit study-related audits and inspections and will provide access to all study-related 
documents (e.g., source documents, regulatory documents, data collection instruments, study 
data, etc.). The Investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
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10.2 
Data Entry and Computerized Systems  
An electronic data capture system will be used in this study. Other data assessments, such as 
central laboratory assays, immunohistochemistry, and ECG data, will be managed by central 
vendors for transfer to MacroGenics, Inc., or representative for use in the study analysis 
database. 
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, computer discs, or tapes. The anonymity of 
participating patients must be maintained. For data collection and data management 
purposes, patients are to be identified by a patient number only. Documents that identify the 
patient beyond patient number will not be submitted to the sponsor (e.g., the signed informed 
consent document; patient initials) and must be maintained in strict confidence by the 
Investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives. 
Site personnel record all data for each study patient through eCRFs using an Electronic Data 
Capture (EDC) system approved by the sponsor. Sites must complete the eCRFs in a timely 
manner and the Investigator must promptly review the completed eCRFs for each patient. As 
the person ultimately responsible for the accuracy of all eCRF data, the Investigator must 
e-sign the Investigator's Statement in each patient's eCRF. The EDC system automatically 
generates queries resulting from the computer checks embedded into the system, so as to 
ensure accuracy, quality, consistency, and completeness of the database. Manual queries 
resulting from review by monitors, medical coders, and other Data Management staff are also 
posted from within the EDC system, where they are tracked. Sites resolve the queries and 
correct the entered data when necessary. Every change to data is captured in the EDC system 
audit trail. Upon completion of the study, each site will be provided with a compact disk 
containing the eCRFs for each of their patients. 
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11 
ADMINISTRATIVE CONSIDERATIONS  
11.1 
Institutional Review Board or Independent Ethics Committee 
Approval  
The Investigator should provide the Sponsor with a statement of compliance from the 
IRB/IEC indicating compliance with the applicable regulations in the region and ICH. Any 
documents that the IRB/IEC may need to fulfill its responsibilities, such as the protocol and 
any amendments, IB, and information concerning patient recruitment, payment or 
compensation procedures, or information from the sponsor will be submitted to the IRB/IEC. 
The IRB/IEC’s written unconditional approval of the study protocol and the informed 
consent forms (ICFs) will be in the possession of the Investigator and the Sponsor before the 
study drug is initiated at the Investigator’s site. The Investigator will transmit the IRB/IEC’s 
unconditional approval statement to the Sponsor. This approval must include the date of 
review, and refer to the study by protocol title and/or study number and version number and 
refer to the ICFs by version number or date. If the IRB/IEC or institution uses its own unique 
number for the protocol instead of the Sponsor’s number, that unique number should be 
noted on the approval statement. If approval of the ICFs is stamped on the forms (instead of 
documented in the IRB/IEC approval statement) the date of approval and/or expiration must 
be included. 
Protocol modifications or changes may not be initiated without approval from the Sponsor 
and prior written IRB/IEC approval (when required), except when necessary to eliminate 
immediate hazards to the patients. Such modifications will be submitted to the IRB/IEC; 
written verification that the modification was submitted should be obtained. 
The Investigator must, where required by local regulations, submit to the IRB/IEC: 
• The protocol and the IB and any amendments or updates. 
• The informed consent form(s) and any amendments or changes. 
• Any documents given to patients or potential patients (e.g., recruitment materials, 
diary cards) and the plan for distribution/use. 
• Revisions of other documents originally submitted for review or for notification. 
• Serious and/or unexpected AEs occurring during the study. 
• New information that may adversely affect the safety of patients or conduct of the 
study. 
• At minimum, an annual update and/or request for re-approval of study, unless 
otherwise specified by IRB/IEC. 
• Protocol violations or deviations 
• Notification when the study has been completed. 
• Proof of indemnity/liability insurance. 
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• Other documents required by the IRB/IEC 
 
11.2 
Ethical Conduct of the Study  
The investigational study will be conducted under a US Investigational New Drug (IND) 
application according to the Protection of Human Subjects United States Code of Federal 
Regulations, Title 21 (21 CFR 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 in accordance with ethical principles that have their origin in 
the Declaration of Helsinki, and all other applicable local regulations and/or guidelines. 
The protocol and the informed consent document will be reviewed and approved by the 
IRB/IEC of each participating center before study initiation. Serious adverse events, 
regardless of causality, will be reported to the Sponsor/designee and to the IRB/IEC, if 
required by local regulations. The Investigator will keep the IRB/IEC informed regarding the 
progress of the study. 
11.3 
Patient Information and Consent  
It is the responsibility of the Investigator to obtain and document written informed consent 
from the patient. Informed consent in compliance with the principles of informed consent in 
ICH E6 and all applicable local regulations should be obtained before any protocol-specified 
procedures or interventions are conducted. The Sponsor reserves the right to delay initiation 
of the study at a site where ICFs do not meet the standards of applicable local regulations or 
ICH E6. 
Information should be given to the patient in both oral and written form, and patients must be 
given ample opportunity to inquire about details of the study. 
The consent form generated by the Investigator must be approved by the IRB/IEC. The 
Investigator will provide the Sponsor with a copy of the IRB/IEC-approved consent forms 
and a copy of the IRB/IEC’s written approval before the start of the study.  
Consent forms must be written (and appropriately translated in the patient’s native language 
or language in which the patient has fluency) so as to be understood by the prospective 
patient. Informed consent will be documented by the use of a written consent form approved 
by the IRB/IEC. The form must be signed and dated by the patient, and by the person who 
conducted the discussion of the informed consent. 
All versions of each patient’s signed ICF must be kept on file by the Investigator for possible 
inspection by regulatory authorities and/or authorized MacroGenics monitoring and 
regulatory compliance persons. The patient should receive a copy of the signed and dated 
written ICF and any other written information provided to the patients. 
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11.4 
Patient Confidentiality  
To maintain confidentiality of patients, all laboratory specimens, evaluation forms, reports, 
and other records will be identified by a coded number. Clinical information will not be 
released without written permission of the patient, except as necessary for monitoring by 
the relevant regulatory authorities, the Sponsor of the clinical 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. 
11.5 
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 onto CRFs designed to capture all observations 
and other data pertinent to the clinical investigation. Data should be recorded on source 
documents and entered onto CRFs. Electronic CRFs should be filled out completely by the 
Investigator or his/her designee. Prior to CRF 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 CRF. The Investigator will retain a copy of all source 
documents. 
11.6 
Access to Source Documentation  
The Investigator and study center will permit the Sponsor, its representatives, IRB, and all 
relevant regulatory agencies access to all original source data and documents regardless of 
media, for study monitoring audits and inspections. 
The Investigator may be subjected to a field audit by MacroGenics, Inc. (or designee), and/or 
regulatory inspectors in order to validate the participation of patients in the study and to 
verify the data reported on the CRFs on file at MacroGenics, Inc. MacroGenics should be 
notified immediately of any audits scheduled by any regulatory authorities. Copies of audit 
reports, findings and/or correspondence from regulatory authorities for audits conducted on a 
MacroGenics-sponsored study should be promptly forwarded to MacroGenics. 
11.7 
Retention of Data  
Per ICH guidelines, all essential documents, including CRFs, source documents (regardless 
of media), signed ICFs, and laboratory test results, should be retained by the Investigator for 
at least 2 years after last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or until at least 
2 years have elapsed since formal discontinuation of clinical development of the 
investigational product. There may be other circumstances for which MacroGenics, Inc., is 
required to maintain study records for longer periods (e.g., applicable local regulations); 
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therefore, MacroGenics, Inc. should be contacted before study records are removed from the 
control of the investigational site for any reason. The Investigator must obtain written 
permission from MacroGenics, Inc., prior to destruction of study documents. 
11.8 
Financial Disclosure  
The Investigator and Sub-Investigators will be required to disclose any applicable financial 
arrangement as defined in US regulation (i.e. 21 CFR 54). The following information will be 
collected: any significant payments of other sorts from MacroGenics, Inc., or any alliance 
partner, such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in margetuximab; and 
any significant equity interest in MacroGenics, Inc., as defined in 21 CFR 54. Investigators 
are obliged to update the Sponsor with any changes in reported information up to 1 year 
following the end of the study (as defined in Section 4.3.2) 
In consideration of participation in the study, MacroGenics, Inc., will pay the Investigator or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
agreement. 
Financial disclosure information will be documented in writing and signed and dated by the 
Investigator. This information will be collected prior to that investigator taking part in the 
research. 
11.9 
Publication and Disclosure Policy  
Data collected in this clinical study belong to the study Sponsor which will formulate a 
policy on the use of study data. This policy will be codified in the Clinical Trial Agreement. 
This includes authorship issues: scheduling and prioritizing analyses for reports, publications, 
and presentations; and developing a review and approval process. 
MacroGenics intends to publish the results of this study in an international peer-reviewed 
journal following completion of all primary endpoints. Interim results may be published prior 
to completion if warranted. If appropriate, results may be presented at scientific conferences 
prior to publication. MacroGenics will adhere to all relevant regulatory guidelines and best 
practices during preparation of any manuscripts or other scientific presentations. 
11.10 
Discontinuation of the Study or Study Sites  
11.10.1 
Discontinuation of Study Sites  
Participation may be discontinued if MacroGenics, Inc., the Investigator, a regulatory 
authority, or the IRB of the study sites deems it necessary for any reason.  
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11.10.2 
Discontinuation of the Study  
The study may be discontinued by a regulatory authority or at the discretion of the Sponsor. 
The study may be terminated if there is evidence of futility, an unacceptable safety signal, or 
failure to achieve a primary endpoint. Patients who are enrolled in the study and continue to 
receive benefit from treatment as defined in the protocol at the time of study termination may 
continue to receive treatment as described until a reason to discontinue treatment is indicated.  
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. 
11.11 
Identification of the Coordinating Principal Investigator  
A Coordinating PI will be appointed by the Sponsor Medical Monitor prior to the end of the 
study.  
As part of his or her responsibilities, the Coordinating PI will review the final Clinical Study 
Report. Agreement with the final Clinical Study Report will be documented by the dated 
signature of the Coordinating PI. 
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4. 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) are to be collected as follows:  at Screening; Cycle 1 Day 1 - before margetuximab or 
trastuzumab infusion, at end of margetuximab or trastuzumab infusion, and at 60 minutes after end of trastuzumab or margetuximab infusion; all subsequent 
Cycles – before and at end of margetuximab or trastuzumab infusions; and at the End of Treatment visit. 
5. 
With Protocol Amendment 4, ECGs will no longer be collected and analyzed centrally. Instead, ECGs will be collected and interpreted locally according to 
institutional standard of care. 
6. 
MUGA or echo to be performed at Screening; Cycle 3 Day 1; Cycle 5 Day 1, and on Day 1 of each 4th cycle thereafter (e.g., Cycles 9, 13, 17) while on treatment; 
and at the End of Treatment visit. Cycle 1 Day 1 MUGA or echo not required if the Screening MUGA scan or echo was performed within 4 weeks of patient 
randomization. MUGA or echo evaluations may be performed up to 14 days prior to the scheduled study visit.  
7. 
HER2 results not required for randomization.  
8. 
Tumor samples may be submitted for HER2 central testing if results are unavailable or if testing was not performed at an appropriate laboratory. 
9. 
Serum pregnancy test results must be obtained within 14 days prior to randomization for women of childbearing potential. 
10. With Protocol Amendment 4, blood and urine samples will no longer be collected and analyzed centrally. Instead, blood and/or urine samples for safety will be 
collected according to institutional standard of care for patients who are receiving a HER2-targeted agent (margetuximab or trastuzumab).  
11. With Protocol Amendment 4, all PK sample collection will be discontinued for patients who are still receiving study treatment at the time of the amendment.  
12. With Protocol Amendment 4, collection of samples for ADA assay will be decreased in frequency from once every 6 weeks (every 2 treatment cycles) to once every 
12 weeks (every 4 treatment cycles), consistent with radiographic imaging. ADA samples will continue to be collected at end of treatment and during follow-up at 3 
months and 6 months following the last dose of margetuximab. ADA samples for the infusion sub-study will be obtained according to the same schedule as the 
margetuximab arm.  
13. Tumor evaluations (radiology and digital imaging of skin lesions) to be performed at Screening and Day 1 of every 2 cycles thereafter for the first 24 weeks of study 
treatment. Following 24 weeks on study treatment, tumor evaluations will be performed every 4 cycles (beginning with Cycle 9) while on treatment or every 3 
months during post-treatment follow-up until documented progression, initiation of alternative anti-cancer therapy, lost to follow-up, withdraw of informed consent, 
death, or end of study. For all patients: CT (with contrast) or MRI of chest, abdomen, and pelvis for all evaluations; bone scan at screening and as clinically 
indicated thereafter. For patients with known, treated brain metastases and/or signs or symptoms of brain metastasis: CT or MRI of brain at Screening only and as 
clinically indicated thereafter. Tumor evaluations may be performed up to 14 days prior to the scheduled study visit. 
14. Information collected to include disease and vital status (including dates of progression and death, if appropriate) and additional cancer treatment(s) received 
following the End of Treatment visit. 
15. Patients to receive one of 4 backbone chemotherapy options (capecitabine, eribulin, gemcitabine, or vinorelbine) to be selected by the investigator (see Section 6.1 
and Table 4.)  Selected chemotherapy must be allowed for use per local regulations. The Day 8 study visit is only required if the patient is assigned to a backbone 
chemotherapy requiring administration on this day. 
16. Margetuximab or trastuzumab may be administered after completion of chemotherapy administration. Two consecutive doses should be a minimum 18 days apart. 
17. Post-treatment Follow-up to occur at 3-month intervals ± 1 week.  
18. Randomization must occur within 72 hours of Cycle 1 Day 1, with dosing preferably on the same day as randomization. 
19. Day 8 evaluations to be performed only if patients are required to return to the study site for administration of backbone chemotherapy. 
20. For Belgium sites only: monthly urine or serum pregnancy tests should be performed locally in women of childbearing potential during the post-treatment follow-up 
period.  
21. Tumor assessments performed as standard of care may be considered baseline and need not be repeated if completed within 4 weeks prior to randomization.  
22. HRQoL assessments are not required for patients assigned to the infusion sub-study. 
 
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Appendix 2 
Principal Investigator’s Agreement  
Study Title: 
A Phase 3, Randomized Study of Margetuximab Plus Chemotherapy vs 
Trastuzumab Plus Chemotherapy in the Treatment of Patients with HER2+ 
Metastatic Breast Cancer Who Have Received Prior Anti-HER2 Therapies and 
Require Systemic Treatment 
Study Number: 
CP-MGAH22-04 
 
I have read the protocol described above.  
I have fully discussed the objectives of this trial and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution of the ethical review of the study, 
without written authorization from MacroGenics, Inc. It is, however, permissible to provide 
information to a patient in order to obtain consent.  
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the trial in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements.  
I understand that the Sponsor may decide to suspend or prematurely terminate the trial at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the trial, I will communicate my 
intention immediately in writing to the Sponsor. 
 
 
Signed: 
 
 
Date:  
 
 
PI Name (printed):  ________________________________________________________ 
PI Affiliation:  ____________________________________________________________ 
PI Address:  ______________________________________________________________ 
PI Phone Number:  ________________________________________________________ 
 
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Appendix 3 
Censoring Rules for Primary PFS Analysis  
Situation 
Date 
Outcome 
No baseline tumor assessments  
Randomization 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 
Randomization date 
Censored 
Documented disease progression 
Date of disease progression 
Progressed 
Initiation of alternative anti-
cancer treatments in absence of 
progression 
Date of last tumor assessment prior 
to initiation of such treatment 
Censored 
Death or progression 
immediately after missing two or 
more consecutive scheduled 
tumor assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
 
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Appendix 4 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work or office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry-on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
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Appendix 5 
NCCN/FACT Breast Symptom Index-16 (FBSI-16)  
 
 
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Appendix 6 
EQ-5D-5L  
 
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Appendix 8 
RECIST 1.1 Guidelines  
(Adapted from Eisenhauer et al. 2009 (9)) 
MEASURABILITY OF TUMOR AT BASELINE 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable 
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable).  
• 20 mm by chest X-ray. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. See also notes below on ‘Baseline documentation of target 
and non-target lesions’ for information on lymph node measurement.  
Non-measurable 
All other lesions, including small lesions (longest diameter < 10mm or pathological lymph 
nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
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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 measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion prior to study enrollment.  
 
SPECIFICATIONS BY METHODS OF MEASUREMENTS 
Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
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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 
examination and imaging, imaging evaluation should be undertaken since it is more objective 
and may also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances.  
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
TUMOR RESPONSE EVALUATION 
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion (as detailed 
above). 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
Where more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
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organs should be identified as target lesions and will be recorded and measured at baseline. 
For example, in instances where patients have only one or two organ sites involved, a 
maximum of two and four lesions respectively will be recorded). Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does not lend 
itself to reproducible measurement in which circumstance the next largest lesions which can 
be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
which are defined as measurable and may be identified as target lesions must meet criterion 
of a short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions 
in the plane in which the image is obtained (for CT scan this is almost always the axial plane; 
for MRI the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as being 20 
mm x30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this 
example, 20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis ≥10 mm but < 15 mm) should be considered non-target lesions. Nodes 
that have a short axis < 10 mm are considered non-pathological and should not be recorded 
or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present,’ ‘absent,’ or in rare cases ‘unequivocal 
progression. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
Response criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
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Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.  
Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is 
also considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm. In order to qualify for CR, each node must achieve a short axis <10 mm. For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum 
of target lesions. 
Target lesions that become ‘too small to measure,’ While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being ‘too small to measure.’ When this occurs it is important that a value be recorded on the 
case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note: It is 
less likely that this rule will be used for lymph nodes since they usually have a definable size 
when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if 
a lymph node is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned in this circumstance as well). This default value is derived 
from the 5 mm CT slice thickness (but should not be changed with varying CT slice 
thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon 
measurement error. However, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment,’ the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesions. If the lesions have 
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truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the ‘coalesced lesion.’ 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesions(s). 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-
target lesions. (Note: the appearance of one or more new lesions is also considered 
progression).  
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When a patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression; on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy. A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of 
target disease will therefore be extremely rare. 
When the patient has only non-measurable disease. The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor 
into the interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy.’ If ‘unequivocal progression’ is seen, 
the patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore, the increase must be substantial. 
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New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal: i.e. not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this 
is the patient who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be 
evidence of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan.  
EVALUATION OF BEST OVERALL RESPONSE 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions.  
Time point response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table 
A-1 on the next page provides a summary of the overall response status calculation at each 
time point for patients who have measurable disease at baseline. 
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will 
have achieved PD status, regardless of the contribution of the missing lesion. 
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Best overall response: all time points 
The best overall response is determined once all the data for the patient is known. 
Table A-1 
Time Point Response: Patients with Target (+/- Non-Target) 
Disease  
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable. 
 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the objective response is 
confirmed on a follow-up scan obtained no less than 4 weeks after the initial scan 
demonstrating an objective response. In this circumstance, the best overall response can be 
interpreted as in Table A-2. 
 
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Table A-2 
Best Overall Response When Confirmation of CR and PR 
Required               
Overall response 
First time point 
Overall response 
Subsequent time point 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD  
CR 
PD 
SD  
CR 
NE 
SD  
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable. 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table A-1 and Table A-2. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
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Amendment 4, 08 June 2020 
 
 
 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.  
CONFIRMATION/DURATION OF RESPONSE 
Confirmation 
Objective responses should be confirmed by CT and/or MRI scans obtained no less than 4 
weeks after the original scan.  
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). The duration of overall complete response is measured 
from the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is 
the reference for calculation of PD.  
 
 
 
 
 
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CP-MGAH22-04 Protocol Amendment 4 (08-Jun-2020)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
esearch Approval (Intended or Designee)
08-Jun-2020 18:35:43 GMT+0000
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
08-Jun-2020 18:40:46 GMT+0000
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SAP_001.pdf: 
Margetuximab 
MacroGenics, Inc. 
CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
STATISTICAL ANALYSIS PLAN 
VERSION 4.0 
PROTOCOL CP-MGAH22-04 
A PHASE 3, RANDOMIZED STUDY OF MARGETUXIMAB PLUS 
CHEMOTHERAPY VS. TRASTUZUMAB PLUS CHEMOTHERAPY IN 
THE TREATMENT OF PATIENTS WITH HER2+ METASTATIC 
BREAST CANCER WHO HAVE RECEIVED PRIOR ANTI-HER2 
THERAPIES AND REQUIRE SYSTEMIC TREATMENT 
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NCT02492711 


Margetuximab 
MacroGenics, Inc. 
CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
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Margetuximab 
MacroGenics, Inc. 
CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................... 6 
1 
INTRODUCTION ........................................................................................................ 8 
1.1 
Data Cutoffs ......................................................................................................... 8 
2 
STUDY OBJECTIVES ................................................................................................. 9 
2.1 
Primary Objective ................................................................................................ 9 
2.2 
Secondary Objectives........................................................................................... 9 
2.3 
Tertiary Objectives ............................................................................................... 9 
2.4 
Exploratory Objective(s) .................................................................................... 10 
3 
STUDY DESIGN AND PLAN ....................................................................................11 
3.1 
Overall Study Design and Plan ...........................................................................11 
3.1.1 
Infusion Sub-Study .................................................................................. 12 
3.2 
Statistical Hypotheses ........................................................................................ 12 
3.3 
Randomization and Sample Size Justification ................................................... 13 
3.3.1 
Randomization and Blinding ................................................................... 13 
3.3.2 
Sample Size Justification ......................................................................... 14 
4 
STUDY POPULATIONS ........................................................................................... 15 
4.1 
Intent-to-Treat Population .................................................................................. 15 
4.2 
Response Evaluable Population ......................................................................... 15 
4.3 
Safety Population ............................................................................................... 15 
5 
ENDPOINTS AND COVARIATES ........................................................................... 16 
5.1 
Efficacy Endpoints ............................................................................................. 16 
5.1.1 
Primary Efficacy Endpoints ..................................................................... 16 
5.1.2 
Secondary Efficacy Endpoints ................................................................. 17 
5.1.2.1 
Investigator-Assessed Progression-Free Survival .......................... 17 
5.1.2.2 
Independent Review-Assessed Objective Response 
Rate................................................................................................. 17 
5.1.3 
Tertiary Efficacy Endpoints ..................................................................... 17 
5.1.3.1 
Duration of Response ..................................................................... 17 
5.1.3.2 
Investigator-Assessed ORR ............................................................ 18 
5.1.3.3 
Clinical Benefit Rate ...................................................................... 18 
5.1.3.4 
NFBSI-16 and EQ-5D-5L HRQoL Surveys ................................... 18 
5.1.3.5 
Population Pharmacokinetics and Exposure-Response 
Relationships .................................................................................. 18 
5.1.3.6 
Anti-Drug Antibodies ..................................................................... 18 
5.1.4 
Exploratory Endpoints ............................................................................. 18 
5.2 
Safety Endpoints ................................................................................................ 19 
5.2.1 
Adverse Events ........................................................................................ 19 
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5.2.2 
Laboratory Evaluations ............................................................................ 20 
5.2.3 
Cardiac Evaluations ................................................................................. 22 
5.2.4 
Physical Examinations ............................................................................. 22 
5.2.5 
Vital Signs ................................................................................................ 22 
5.2.6 
Pharmacokinetic and Immunogenicity Evaluations ................................. 22 
5.2.7 
Covariates and Stratification Factors ....................................................... 22 
6 
STATISTICAL METHODOLOGY ............................................................................ 24 
6.1 
General Considerations ...................................................................................... 24 
6.1.1 
Interim Analyses ...................................................................................... 24 
6.1.2 
Missing Data ............................................................................................ 26 
6.2 
Standard Summaries and Analyses .................................................................... 26 
6.2.1 
Demographics, Baseline Characteristics, and Cancer History ................. 26 
6.2.2 
Study Drug Exposure ............................................................................... 27 
6.3 
Efficacy Endpoint Analyses ............................................................................... 28 
6.3.1 
Primary Endpoint Analyses ...................................................................... 28 
6.3.1.1 
Progression Free Survival and Overall Survival – 
Primary Analyses............................................................................ 28 
6.3.1.2 
Sensitivity Analyses for Progression Free Survival and 
Overall Survival ............................................................................. 30 
6.3.2 
Secondary and Selected Tertiary Endpoint Analyses ............................... 31 
6.3.2.1 
Investigator-Assessed PFS ............................................................. 31 
6.3.2.2 
Objective Response Rate, Duration of Response, and 
Clinical Benefit Rate ...................................................................... 31 
6.3.2.3 
NFBSI-16 and EQ-5D-5L .............................................................. 32 
6.3.3 
Exploratory Analyses ............................................................................... 33 
6.3.4 
Population Pharmacokinetics, Exposure-Response 
Relationships, and Anti-Drug Antibodies ................................................ 34 
6.4 
Safety Endpoint Analyses .................................................................................. 34 
6.4.1 
Adverse Events ........................................................................................ 34 
6.4.2 
Laboratory Values .................................................................................... 36 
6.4.3 
Electrocardiograms, Multi-Gated Acquisition Scans, Physical 
Examinations, and Vital Signs ................................................................. 37 
6.5 
Data Standards ................................................................................................... 39 
7 
DATA HANDLING CONVENTIONS ....................................................................... 40 
8 
REFERENCES ........................................................................................................... 41 
 
LIST OF TABLES 
Table 1 
Censoring Rules for Primary PFS Analysis .................................................. 16 
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Margetuximab 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
Table 2 
Laboratory Parameters .................................................................................. 21 
Table 3 
Example of Efficacy Boundaries at Planned Interim and Final 
Analyses ....................................................................................................... 25 
Table 4 
Demographics ............................................................................................... 27 
Table 5 
Summary of Drug Exposure ......................................................................... 28 
Table 6 
Primary Endpoint Summaries ....................................................................... 29 
Table 7 
ORR, DOR, and CBR Summaries ................................................................ 32 
Table 8 
HRQoL Summaries ...................................................................................... 33 
Table 9 
Summary of PK and Anti-Drug Antibodies - Margetuximab ....................... 34 
Table 10 
Adverse Event Summaries ........................................................................... 36 
Table 11 
Summary of Laboratory Parameters ............................................................. 37 
Table 12 
Summary of ECG, Vital Signs, and MUGA Results ..................................... 38 
 
 
 
 
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Margetuximab 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
LIST OF ABBREVIATIONS 
 
ADA  
 
Anti-drug antibody 
ADaM  
 
Analysis Dataset Model 
AE  
 
 
Adverse event 
AESI  
 
Adverse event of special interest 
CBR  
 
Clinical benefit rate 
CDISC 
 
Clinical Data Interchange Standards Consortium 
CDST  
 
CRO DSMC Support Team 
CR  
 
 
Complete response 
CRO  
 
Clinical Research Organization 
CT  
 
 
Computed tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events  
DOR  
 
Duration of response 
DSMC  
 
Data Safety Monitoring Committee 
ECG  
 
Electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
eCRF  
 
Electronic case report form 
E-R 
 
 
Exposure-response 
ER  
 
 
Estrogen receptor 
HR  
 
 
Hazard ratio 
HRQoL 
 
Health related quality of life 
IHC 
 
 
immunohistochemistry 
IRE 
 
 
Immediately reportable events 
ISH 
 
 
in situ hybridization 
ITT 
 
 
Intent-to-treat 
IxRS  
 
Interactive Response System 
LVEF  
 
Left ventricular ejection fraction 
MedDRA  
Medical dictionary for regulatory activities 
MMRM 
 
Mixed model repeated measures 
MRI 
 
 
Magnetic resonance imaging 
MUGA 
 
Multi Gated Acquisition Scan 
NCI 
 
 
National Cancer Institute 
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Margetuximab 
MacroGenics, Inc. 
CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
NFBSI 
Network-Functional Assessment of Cancer Therapy – Breast Cancer 
Symptom Index 
ORR  
 
Objective response rate 
OS  
 
 
Overall survival 
PFS 
 
 
Progression-free survival 
PK  
 
 
Pharmacokinetics 
PT  
 
 
Preferred Term 
PR  
 
 
Partial response 
PgR 
 
 
Progesterone receptor 
RE  
 
 
Response-Evaluable 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
SAE 
 
 
Serious adverse event 
SAS 
 
 
Statistical Analysis System 
SD  
 
 
Stable disease 
SD  
 
 
Standard deviation 
SOC  
 
System Organ Class 
SDTM  
 
Study Data Tabulation Model 
TEAE  
 
Treatment emergent adverse event 
T-DM1 
 
Ado-trastuzumab emtansine  
TLF 
 
 
Table, listing and figure 
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Margetuximab 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
1 
 INTRODUCTION 
This document describes the details of the statistical analyses, data summaries, and data 
conventions to be used for study CP-MGAH22-04. This Phase 3 study was designed to 
compare the efficacy and safety of the margetuximab plus chemotherapy to trastuzumab plus 
chemotherapy in patients with HER2+ metastatic breast cancer who have received at least 
two prior lines of anti-HER2 directed therapies in the metastatic setting, or in case of having 
received (neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the 
metastatic setting, and who have received at least one, and no more than three, lines of 
therapy overall in the metastatic setting. Analyses and summaries are described to allow for 
statistically meaningful conclusions to be drawn from this study. 
CP-MGAH22-04 also includes a sub-study cohort to evaluate the safety and tolerability of 
sequential reductions in margetuximab infusion duration from 120 minutes in Cycle 1 to 30 
minutes in Cycle 2 and beyond. Patients who participate in the infusion sub-study will not be 
randomized and will be enrolled to receive either monotherapy margetuximab or 
margetuximab in combination with protocol-specified physician’s choice of chemotherapy. 
Patients must have received at least 4 prior lines of therapy for metastatic disease to be 
eligible for the infusion sub-study, therefore the patient population will not overlap with the 
randomized portion of CP-MGAH22-04.  
1.1 
Data Cutoffs 
This randomized study includes two primary endpoints, progression-free survival (PFS) and 
overall survival (OS) that are anticipated to be assessed at different time points. Two 
assessments for PFS will be made: 1) PFS will be assessed for futility when approximately 
100 PFS events have occurred and 2) the primary PFS analysis will take place when 
approximately 257 PFS events have occurred or after all planned patients (N=530) have been 
randomized, whichever occurs later.  
The first interim OS analysis will occur at the time of the primary PFS analysis. A second 
interim analysis for OS will be performed when 70% of the target OS events have occurred if 
this has not yet occurred at the time of the primary PFS analysis.  
A data cutoff date corresponding to the PFS analyses (futility and final) and interim OS 
analyses will be established and the data domains required for each analysis will be locked 
and datasets extracted. All visit dates up to this date will be included. Partial dates will follow 
the rules described in Section 6.1.2. Durations for end dates that have not occurred will be 
censored.  
The final analysis for OS will be conducted when approximately 385 deaths have occurred. A 
final database lock will occur at this time. 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy, as measured by PFS assessed 
by independent review and OS, of margetuximab plus chemotherapy compared to 
trastuzumab plus chemotherapy in patients with advanced HER2-positive breast cancer who 
have received at least two prior lines of anti-HER2 directed therapies in the metastatic 
setting, or in case of having received (neo)adjuvant pertuzumab, at least 1 prior line of anti-
HER2 directed therapy in the metastatic setting, and who have received at least one, and no 
more than three, lines of therapy overall in the metastatic setting. In either case, patients must 
have received prior treatment with pertuzumab in the (neo)adjuvant or metastatic setting. 
Infusion Sub-Study: The primary objective of the infusion sub-study is to determine the 
safety and tolerability of margetuximab administered at a reduced infusion time in Cycle 2 
and beyond. The incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end 
of Cycle 2 is the primary outcome measure. 
 
2.2 
Secondary Objectives  
The secondary objectives are:   
 To evaluate PFS, as assessed by the study investigators, of margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
 To evaluate by independent review, the objective response rate (ORR) of 
margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in these 
patients. 
 
Infusion sub-study: Incidence of all Grade infusion-related reactions in all sub-study patients 
is the secondary outcome measure. 
 
2.3 
Tertiary Objectives  
The tertiary objectives are: 
 To evaluate the health-related quality of life (HRQoL), as assessed using the 
Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom 
Index (NFBSI-16) and EQ-5D-5L, associated with margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
 To characterize the safety profile of margetuximab plus chemotherapy vs. 
trastuzumab plus chemotherapy in these patients. 
 To evaluate the clinical benefit rate (CBR) of margetuximab plus chemotherapy 
vs. trastuzumab plus chemotherapy in these patients. Both independently assessed 
and investigator assessed CBR will be evaluated. 
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 To evaluate ORR, as assessed by study investigators, of margetuximab plus 
chemotherapy vs. trastuzumab plus chemotherapy in these patients. 
 To evaluate the duration of response (DOR) of margetuximab plus chemotherapy 
vs. trastuzumab plus chemotherapy in these patients. Both independently assessed 
and investigator assessed DOR will be evaluated. 
 To characterize the population pharmacokinetics and exposure-response (E-R) 
relationships of margetuximab in these patients. 
 To evaluate the anti-drug antibodies (ADA) directed against margetuximab and its 
effects on pharmacokinetics (PK), efficacy, and safety in these patients. 
 
2.4 
Exploratory Objective(s) 
To evaluate the effect of allelic variation in CD16A, CD32A, and CD32B on the efficacy of 
margetuximab in all patients receiving study treatments.  
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
3 
STUDY DESIGN AND PLAN 
3.1 
Overall Study Design and Plan 
This is a randomized, Phase 3, open-label, comparator-controlled study comparing 
margetuximab to trastuzumab, each in combination with chemotherapy, for the treatment of 
patients with advanced HER2+ breast cancer who have received at least two prior lines of 
anti-HER2 directed therapies in the metastatic setting, or in case of having received 
(neo)adjuvant pertuzumab, at least 1 prior line of anti-HER2 directed therapy in the 
metastatic setting, and who have received at least one, and no more than three, lines of 
therapy overall in the metastatic setting. Patients must have progressed on or following the 
most recent therapy. Eligible patients will be assigned to chemotherapy of the investigator’s 
choice to be chosen from capecitabine, eribulin, gemcitabine, or vinorelbine. The selected 
chemotherapy must be allowed for use per local regulations. Upon meeting entry criteria, 
patients enrolled in the study will be randomized 1:1 to receive either margetuximab or 
trastuzumab to be administered in combination with the chosen chemotherapy. Patients will 
be treated until disease progression, death, withdrawal of consent, or request by the treating 
physician to discontinue treatment. Following completion of (or discontinuation from) 
treatment, patients will be followed for survival. 
Randomization will be stratified by backbone chemotherapy regimen, number of metastatic 
sites, and number of lines of therapy in the metastatic setting. Patients will receive either 
margetuximab or trastuzumab on Day 1 of a 3-week cycle. Chemotherapy will be given prior 
to margetuximab or trastuzumab on days when both study drug and chemotherapy are 
administered. 
Tumor evaluations will be performed according to the schedules outlined in the latest version 
of the protocol. Disease response will be determined both locally and by central review using 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patient treatment decisions 
will be based on local (investigator) reviews of available assessments. Central radiological 
and medical review will be conducted by BioClinica and will be blinded to the study 
treatment (margetuximab or trastuzumab). Results of central review will be used for the 
primary endpoint of PFS.  
A Data Safety Monitoring Committee (DSMC) will monitor safety throughout the 
randomized portion of the trial and perform interim analyses for PFS and OS at prespecified 
time points. The DSMC will perform a futility analysis after 100 PFS events have occurred, 
and will perform two interim analyses of OS: one at the time of the primary assessment of 
PFS and a second when 70% of the OS events have occurred. The role and function of the 
DSMC are described more fully in the DSMC Charter. 
The primary PFS analysis will occur when approximately 257 PFS events have occurred or 
after all patients have been randomized, whichever occurs last. The final OS analysis will be 
conducted when 385 deaths have been reported. 
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Margetuximab 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
3.1.1 
Infusion Sub-Study  
CP-MGAH22-04 will include a non-randomized sub-study cohort of about 78 patients to 
evaluate safety and tolerability of margetuximab infusion duration reduction from 120 
minutes in Cycle 1 to 30 minutes in Cycle 2 and beyond. The sub-study will start with a run-
in group, in which about 9 patients will receive a 120-minute margetuximab infusion (as a 
single agent, or in combination with protocol-specified chemotherapy) in Cycle 1, in order to 
have 6 patients receive 60-minute infusions in Cycle 2 and beyond (Stage A1). If no stopping 
rules are met, an additional cohort of about 9 patients will be enrolled to receive a 120-
minute margetuximab infusion in Cycle 1, in order to have 6 patients receive a 30-minute 
infusions at Cycle 2 and beyond (Stage A2). Patients enrolled into Stage A1 and A2 will be 
assigned to receive the reduced infusions until 6 patients have received reduced infusion 
times. Any extra patients beyond 6 in run-in groups A1 or A2 will continue 120-minute 
infusions until the Stage B regimen is confirmed. In the absence of Grade 3 or higher IRRs, 
patients in Stage A may reduce infusion duration to the Stage B regimen. 
 
Safety events observed in Stage A1 and A2 will be used to inform infusion reduction 
schemes for a subsequent group of about 60 patients enrolled to Stage B, who will receive 
margetuximab over a 120-minute infusion in Cycle 1, followed by either a 60-minute or 30-
minute infusion in Cycles 2 and beyond. Details of the study design and stopping rules can 
be found in Section 6.7.1 and Figure 1 of the latest version of protocol (CP-MGAH22-04 
Protocol Amend 3, dated 26 January 2018). 
 
3.2 
Statistical Hypotheses 
The primary endpoints of centrally-assessed PFS and OS will be compared between groups 
and tested in sequential order. PFS will be tested first. If PFS is statistically significant, only 
then will OS be tested. Both hypotheses will be evaluated at α = 0.05. 
The null hypothesis for each endpoint is that the two treatment arms are the same. The 
alternative hypothesis is that the survival distributions of both PFS and OS are different. 
The null and alternative hypotheses to be tested for PFS: 
Ho: PFST = PFSM,     
H1: PFST ≠ PFSM  
AND 
The null and alternative hypotheses to be tested for OS: 
Ho: OST = OSM,     
H1: OST ≠ OSM  
For the above hypotheses: T = trastuzumab plus chemotherapy, M = margetuximab plus 
chemotherapy. Rejecting either the PFS null hypothesis or both the PFS and OS null 
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hypotheses will be considered sufficient for achieving the study’s primary objective. If the 
PFS null is not rejected, based on the hierarchical approach, OS cannot be tested. 
3.3 
Randomization and Sample Size Justification 
3.3.1 
Randomization and Blinding 
Approximately 530 patients will be randomized 1:1 to either margetuximab plus 
chemotherapy or trastuzumab plus chemotherapy via an Interactive Response System (IxRS) 
within 3 days of Study Day 1 (Cycle 1 Day 1).  
Central randomization will be used. Blocked randomization will be used to achieve treatment 
balance within each stratum.  
The stratification factors are: 
 Choice of backbone chemotherapy 
o Capecitabine 
o Eribulin 
o Gemcitabine 
o Vinorelbine 
 
 Number of metastatic sites 
o ≤2 
o >2 
 
 Number of lines of prior therapy in the metastatic setting 
o ≤2 
o >2 
 
This is an open-label Sponsor-blinded study. Patients and investigators will not be blinded to 
treatment assignment. However, clinical data with respect to treatment assignment will 
remain blinded to the Sponsor and certain contract research organization (CRO) staff unless 
unblinding is required for operational aspects of the study. Specifically, all Sponsor and CRO 
staff directly involved in the conduct of data analyses will remain blinded. Unblinding will 
occur at the time of the final PFS analysis. 
Infusion sub-study: The sub-study will be single arm and unblinded. Patients who participate 
in the infusion sub-study will be enrolled to receive either monotherapy margetuximab or 
margetuximab in combination with protocol-specified physician’s choice of chemotherapy 
(capecitabine, eribulin, gemcitabine, or vinorelbine). 
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Margetuximab 
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CP-MGAH22-04: Statistical Analysis Plan 
Version 4.0, 13 March 2018 
 
 
3.3.2 
Sample Size Justification  
This study has two primary endpoints. The first primary endpoint is centrally-assessed PFS 
and the second primary endpoint is OS. These two endpoints will be assessed in a sequential 
order with PFS being assessed first. OS will only be assessed if a statistically significant 
difference is obtained in PFS. 
It is estimated that the median PFS for patients treated with trastuzumab plus chemotherapy 
is approximately 4 months. To detect a 2 month improvement in median PFS from 4 months 
to 6 months (HR=0.67) in patients treated with margetuximab plus chemotherapy, assuming 
that PFS is exponentially distributed, a total of 257 PFS events are required to provide 90% 
power at a 2-sided α=0.05. The analysis of the primary PFS endpoint will occur when about 
257 events have occurred or after all patients have randomized, whichever occurs later. The 
sample size for this study is calculated to ensure 80% power for the analysis of OS. The 
median OS for patients treated with trastuzumab plus chemotherapy is estimated to be 
12 months. This study is designed to detect an increase to a median survival of 16 months in 
patients treated with margetuximab plus chemotherapy (HR=0.75). Assuming that OS is 
exponentially distributed with median OS time of 12 months for trastuzumab plus 
chemotherapy arm and 16 months for margetuximab plus chemotherapy arm, 2 interim 
analyses are performed as described in Section 6.1.1, and a Lan-DeMets alpha spending 
function using an O’Brien-Fleming stopping boundary is used, approximately 385 deaths will 
be required to provide 80% power to achieve statistical significance at overall type I error of 
2-sided alpha=0.05. It is anticipated that approximately 530 patients will be accrued to 
achieve this number of events.  
The planned sample size for the infusion sub-study is approximately 78 patients, including 
about 18 patients for Stage A and 60 patients for Stage B. A target sample size of 60 patients 
for Stage B of the infusion sub-study is intended to provide confirmation of accelerated 
infusion tolerability.  
Total trial enrollment, including randomized and infusion sub-study cohorts, is expected to be 
approximately 608. 
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CP-MGAH22-04: Statistical Analysis Plan 
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4 
STUDY POPULATIONS 
4.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population represents all randomized patients. Patients will be 
analyzed according to the treatment assigned at randomization. This population will be used 
to summarize baseline data and for the assessment of PFS, OS, and HRQoL.  
4.2 
Response Evaluable Population 
The Response-Evaluable (RE) population represents all patients who are randomized and 
have measurable disease at baseline. This population will be used for ORR and CBR.  
4.3 
  Safety Population 
The Safety population represents patients who are randomized and receive any amount of 
study treatment. Patients will be analyzed according to the actual treatment received rather 
than the treatment group to which they were randomized. This population will be used for 
safety, PK, pharmacodynamics, and immunogenicity analyses. 
Infusion sub-study: The safety population for the infusion sub-study represents patients who 
are enrolled in the infusion sub-study and receive any amount of study treatment. This 
population will be used for all analyses for patients enrolled and treated in the infusion sub-
study described in Section 6 below. 
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CP-MGAH22-04: Statistical Analysis Plan 
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5 
ENDPOINTS AND COVARIATES 
5.1 
Efficacy Endpoints 
5.1.1 
Primary Efficacy Endpoints 
The primary endpoints are independently-assessed PFS and OS. PFS is defined as the time 
from the date of randomization to date of first documented progression or date of death from 
any cause, whichever occurs first. For patients who are not known to have died or progressed 
at the time of data cut-off for PFS analysis, the PFS will be censored at the last tumor 
assessment. The documented progression is determined by radiographic assessment using 
RECIST v1.1. PFS will be calculated as: 
PFS (months) = round ((date of progression or date of death or date of last tumor assessment 
– date of randomization+1) / (365.25/12), .01) 
 
The following table describes the censoring rules for the primary PFS analysis. 
Table 1 
Censoring Rules for Primary PFS Analysis 
Situation 
Date 
Outcome 
No baseline tumor assessments  
Randomization date 
Censored 
Death prior to 1st scheduled tumor 
assessment 
Date of death 
Progressed 
No post-baseline tumor 
assessments in absence of death 
prior to first scheduled tumor 
assessment 
Randomization date 
Censored 
Documented disease progression 
Date of disease progression 
Progressed 
Initiation of alternative anti-
cancer treatments in absence of 
PD 
Date of last tumor assessment prior 
to initiation of such treatment 
Censored 
Death or progression immediately 
after missing two or more 
consecutive scheduled tumor 
assessments 
Date of last tumor assessment prior 
to missed assessments 
Censored 
 
The OS time is defined as the time from date of randomization 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 were last known to be alive. OS will be calculated 
as: 
OS (months) = round ((date of last known alive or death date – date of randomization+1) 
/ (365.25/12), .01)  
Since the endpoints are evaluated in a hierarchical manner, both endpoints will be assessed 
using a 2-sided α = 0.05. 
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5.1.2 
Secondary Efficacy Endpoints 
Two secondary endpoints are defined and will be assessed using a 2-sided α = 0.05. 
To control the type 1 error rate at 0.05 for these 2 secondary endpoints, Hochberg’s step-up 
method will be used. P-values will be assessed in descending order. If the least significant p-
value<0.05, both hypotheses are rejected. Otherwise, this endpoint is retained and the second 
p-value is tested at p<0.025. If a p-value<0.025 (0.05/2) is obtained, this hypothesis is 
rejected. Otherwise, both hypotheses are retained. 
5.1.2.1 
Investigator-Assessed Progression-Free Survival 
Investigator-assessed PFS will be defined in the same manner as independently-assessed 
PFS. The only difference is that disease progression will be determined by the investigator 
instead of by independent assessment via central radiographic review.  
5.1.2.2 
Independent Review-Assessed Objective Response Rate 
Tumor measurements will be assessed using RECIST 1.1 criteria based on independent 
radiological review. A responder is a patient with baseline measurable disease who achieves a 
complete response (CR) or partial response (PR) that is confirmed at least 28 days after the 
initial documentation of an objective response. Patients who have baseline measurable 
disease but no post-baseline radiographic assessment will be considered as non-responders. 
Response rate will be calculated as: 
ORR = # patients with confirmed response (CR or PR) / # patients in the RE population  
5.1.3 
Tertiary Efficacy Endpoints 
A number of tertiary endpoints will be assessed. No adjustment for multiplicity will be used 
for these endpoints. 
5.1.3.1 
Duration of Response 
DoR will be based on both independent review and investigator assessed responses (CR or 
PR). It is defined as time from initial response to date of progression or death from any 
cause, whichever occurs first. DoR will be analyzed for responding patients only. For 
responding patients who are not known to be dead or progressed at the time of data cut-off 
for DoR analysis, the DoR will be censored at the last tumor assessment. 
DoR will be calculated as:  
DoR(months) = round ((progression date or death date or date of last tumor assessment   
– date of initial response+1) / (365.25/12),0.01) 
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5.1.3.2 
Investigator-Assessed ORR 
Investigator assessed ORR is calculated the same as in Section 5.1.2.2. The only difference is 
that the response is determined by study investigators. 
5.1.3.3 
Clinical Benefit Rate 
The CBR is defined as the number of patients in the RE population who achieve a best 
response of CR, PR, or stable disease (SD) of duration >6 months. It will be evaluated based 
on both independent review assessed and investigator assessed responses. 
CBR will be calculated as: 
CBR = # patients with best response CR, PR, SD >6 months / # patients in RE population  
5.1.3.4 
NFBSI-16 and EQ-5D-5L HRQoL Surveys  
Quality of life data will be collected from direct reports from patients on the randomized 
portion of CP-MGAH22-04 using the NFBSI-16 and EQ-5D-5L questionnaires. The primary 
analysis of NFBSI-16 will be based on the total score with secondary analyses of the 
subscales that add to the total. Analysis of EQ-5D-5L will be based on both the EQ-5D utility 
index and the EQ-5D VAS score.  
These data will be collected according to the schedules outlined in the latest version of the 
protocol. 
To help reduce missing data, intensive training of the sites, central monitoring of the timely 
completion of the questionnaires, and regular communication with the sites will be 
performed. 
5.1.3.5 
Population Pharmacokinetics and Exposure-Response 
Relationships 
Serum concentrations of margetuximab will be collected according to the schedules outlined 
in the latest version of the protocol. Single and multiple dose PK parameters for 
margetuximab (Cmax, Tmax, AUCtau, AUCinf, Ctrough, CL, Vss, and Thalf) will be derived from 
margetuximab serum concentration versus time data. 
5.1.3.6 
Anti-Drug Antibodies 
ADA samples will be collected according to the schedules outlined in the latest version of the 
protocol. Samples will be classified as negative or positive and summarized as such. 
5.1.4 
Exploratory Endpoints 
Associations between efficacy endpoints (response, PFS and OS) and respective alleles 
coding for CD16A (VV, FF, and VF), CD32A (HH, RR, HR), and CD32B (II, TT, and IT) 
may be explored. Specifically, logistic regression model for response, and Cox proportional 
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hazards model for PFS and OS, respectively, may be applied with treatment, each protein, 
and their interactions being included as covariates. In particular, for protein CD16A, the 
alleles coding will be grouped as VV vs (VF and FF) in the models to assess the treatment 
effect difference in VV vs (VF and FF).  
In addition, the impact of subsequent use of T-DM1 (after discontinuing from SOPHIA 
treatment) on the efficacy endpoint OS will be evaluated by time-dependent Cox model. 
5.2 
Safety Endpoints 
5.2.1 
Adverse Events 
Safety and tolerability will be assessed from time of study drug initiation through the End of 
Treatment visit (or 28 days after the last dose of study drug, whichever occurs later). Safety 
will be evaluated primarily by summarizing adverse events (AEs), immediately reportable 
events (IREs), adverse events of special interest (AESIs), and serious adverse events (SAEs). 
Adverse events will be summarized by System Organ Class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA v18.0 or higher). Events 
will be summarized by severity (using the National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE] version 4.03 or later) and relationship to 
study drug (as assessed by the investigator). Patients will be counted only once for each 
preferred term, once for each system organ class or AESI and by the highest event severity, 
regardless of how many events the subject experienced.  
These events will be recorded by the Investigators in the electronic case report forms 
(eCRFs). Verbatim terms will be coded to lower-level terms in the MedDRA coding 
dictionary. 
Only treatment-emergent adverse events (TEAEs) will be summarized in tables. Events that 
occur prior to first dose will not be included in these summaries (unless the event worsens 
post first dose) but will be included in patient listings. In addition, events related to tumor 
progression/worsening of underlying disease (including those with a fatal outcome) will be 
collected as efficacy endpoints, and not documented as AEs/SAEs. A TEAE is defined as any 
event that is newly occurring after the first administration of study drug or an event that 
existed at the time of first study drug administration but increased in severity after study drug 
administration. An ongoing TEAE that changes in severity (increases or decreases) will be 
captured as a new event.  
The AESIs will include: 
 All infusion-related reactions; only Grade 3 or greater will be reported as 
Immediate Reportable Events.  
 Left ventricular dysfunction requiring delay or cessation of margetuximab or 
trastuzumab administration. 
 
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Infusion sub-study: AEs, IREs, AESIs, and SAEs will be summarized as described above. In 
particular, the safety and tolerability of reduced margetuximab infusion times will be 
assessed based on: 
 Incidence of Grade 3 or greater IRRs by the end of Cycle 2 in Stage B patients who 
received a Cycle 2 dose at a lowered infusion rate (primary outcome measure).  
 Overall incidence of all Grade IRRs in all sub-study patients (secondary outcome 
measure).  
 
5.2.2 
Laboratory Evaluations   
Standard safety laboratory parameters collected via a central laboratory will be summarized 
and graded according to CTCAE Version 4.03. Lab values falling outside of a clinically 
accepted reference range or values that differ significantly from previous values will be 
evaluated for clinical significance. If a value is considered as an abnormal change from 
baseline and of clinical significance, it is considered as an AE. Table 2 identifies the routine 
laboratory tests that will be performed. 
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Table 2 
Laboratory Parameters 
Pregnancy test 
 
Blood serum human chorionic gonadotropin 
(hCG)  
 
Hematology: 
 
Hematocrit (Hct) 
 
Hemoglobin (Hgb) 
 
Platelet count 
 
Red blood cell (RBC) count  
 
White blood cell (WBC) count with 
differential counts 
 
Serum Chemistry: 
 
Albumin (ALB) 
 
Alkaline phosphatase (ALK-P) 
 
Alanine aminotransferase (ALT; SGPT) 
 
Aspartate aminotransferase (AST; SGOT) 
 
Amylase 
 
Bicarbonate 
 
Blood urea nitrogen (BUN) 
 
Total Bilirubin (direct and indirect) 
 
Calcium (Ca) 
 
Chloride (Cl) 
 
Creatinine 
 
Glucose 
 
Magnesium 
 
Lactate dehydrogenase (LDH) 
 
Lipase 
 
Phosphorus 
 
Potassium (K) 
 
Sodium (Na) 
 
Total protein 
Coagulation:  
 
Prothrombin time (PT) 
 
Activated partial thromboplastin time (aPTT) 
 
Urinalysis:  
 
Bilirubin 
 
Glucose 
 
Ketones 
 
Nitrite  
 
Occult blood 
 
pH 
 
Protein 
 
Specific gravity 
 
Urobilinogen 
 
Leukocytes 
 
 
 
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5.2.3 
Cardiac Evaluations 
Twelve-lead surface electrocardiograms (ECGs) will be obtained according to the schedules 
outlined in the latest version of the protocol.  
ECGs will be obtained in triplicate. Means from these 3 replicates will be used for analysis. 
The following continuous endpoints will be summarized:  
 Heart rate 
 QT interval 
 QTcB (Bazett’s correction) = QT /√ RR 
 QTcF (Fridericia’s correction) = QT / RR^ (1/3)  
 
These derived values will be provided in the data from the central ECG vendor. While both 
QTcB and QTcF are expected to be available, analysis will be based on QTcF. 
MUGA scanning or echocardiogram will be obtained according to the Appendix 1 Schedule 
of Events in the latest version of protocol. Only left ventricular ejection fraction (LVEF) data 
will be collected and evaluated. 
Abnormalities will be reported as AEs and summarized as such. 
5.2.4 
Physical Examinations  
Physical examinations will be performed according to the schedules outlined in the latest 
version of the protocols. Abnormalities that were not present prior to dosing will be captured 
and summarized as adverse event data. Those present prior to dosing will be included as 
medical history. 
5.2.5 
Vital Signs  
Vital sign assessments will be performed according to the schedules outlined in the latest 
version of the protocol. Abnormalities such as drops in blood pressure and high temperatures 
that are measured at any time will be graded according to criteria in the CTCAE.  
5.2.6 
Pharmacokinetic and Immunogenicity Evaluations  
PK samples and ADA samples will be collected according to the schedules outlined in the 
latest version of the protocol.  
5.2.7 
Covariates and Stratification Factors 
As stated in Section 3.3.1, randomization will be stratified by backbone chemotherapy, 
number of metastatic sites, and number of lines of therapy in the metastatic setting. If a 
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patient is mistakenly randomized into an incorrect stratum, then that patient will nonetheless 
be analyzed as a part of that stratum. 
These 3 factors will be the stratification factors used for the stratified analyses described in 
Section 6.3.1. 
Data will be pooled across regions and centers. 
Patients who participate in the infusion sub-study will not be stratified nor randomized.  
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6 
STATISTICAL METHODOLOGY 
6.1 
General Considerations 
All statistical inferences will be based on two-sided tests. 
Categorical data will be summarized by the number and percent of patients falling within 
each category. Continuous variables will be summarized by descriptive statistics, including 
mean, standard deviation (SD), median, minimum, and maximum. 
Unless otherwise noted, continuous variable summaries will be summarized with one more 
significant digit than the original values. P-values will be reported in 0.XXXX format where 
XXXX represent the value rounded to four decimal places. Any p-value <0.0001 will be 
presented as <0.0001. 
If needed, data will be provided in data listings sorted by treatment, patient ID and study 
visit. Summary tables will be by treatment group (margetuximab plus chemotherapy, 
trastuzumab plus chemotherapy). 
Study Day 1 is defined as the first day of study drug administration. A 3-day window is 
allowed between randomization and dosing. If randomization and dosing do occur on 
separate days, randomization day will be defined as: Study Day -2, -1, 0. In all cases, 
endpoints that are time related (OS, PFS) will be determined from time of randomization. 
Unless otherwise noted, baseline values will be defined as the most recent value collected 
prior to the first dose of study drug.  
Data summaries and tabulations will be conducted using SAS® software Version 9.3 or 
higher. Note that the tables, listings and figures (TLFs) listed in each section below are not 
meant to be exhaustive. Rather they represent current overview of which data will be 
presented in TLFs. To avoid an unnecessary SAP amendment, a separate document will be 
used to capture all these TLFs and their modifications, if any, as well as any additional TLFs 
as appropriate. 
All analyses described in subsequent sections are intended for the randomized portion of the 
study. Analyses that also apply to the infusion sub-study will be specified in applicable 
sections.  
6.1.1 
Interim Analyses 
A charter will be prepared and signed off by DSMC members prior to study start. They will 
be supported by the CRO DSMC Support Team (CDST) who will be unblinded as needed 
and will not interact unnecessarily with study team members who are blinded to the trial. 
When approximately 100 of the planned PFS events have occurred, a futility analysis will be 
performed. Futility will be assessed using conditional power conducted both under the initial 
study design and under the current trend of the data. The hazard ratio (HR) used in the 
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calculation will be derived from stratified Cox proportional hazards model. The CDST 
biostatistician supporting the DSMC will provide these calculations. 
The DSMC may consider recommending termination of the study if conditional power is 
low, such as <20%. However, the DSMC will use the conditional power assessment, safety 
evaluations, and study conduct considerations (e.g., recruitment, design assumptions, 
protocol adherence/deviations, dropout rate, data quality, etc.) in their evaluation.  
The DSMC will also perform a maximum of three efficacy evaluations for the OS endpoint. 
The first evaluation will be at the time of the PFS assessment endpoint, the second will occur 
when approximately 70% of the OS events have occurred if the OS endpoint has not been 
reached at the time of the PFS assessment and lastly if not reached at the second interim, at 
the time of study completion when approximately 385 OS events have occurred. The Lan-
DeMets alpha spending function using an O’Brien-Fleming stopping boundary will be used 
to control overall type I error at 2-sided 0.05. The efficacy boundaries based on this method 
will depend on the actual observed number of OS events at each analysis and hence will be 
calculated and provided to DSMC once the actual number of OS events is known for each 
interim analysis. For example, if we observe 139 OS events (as expected per simulation) at 
the time of observing 257 PFS events for the primary PFS analysis, then the efficacy 
boundaries at each interim and final analysis are as follows (ADDPlan v6, with O’Brien-
Fleming type alpha spending function and Schoenfeld formula for sample size calculation). 
Table 3 
Example of Efficacy Boundaries at Planned Interim and Final 
Analyses 
Analysis 
Timing of Analysis 
Observed number (% of 
information fraction) of 
OS Events at Each 
Analysis 
Efficacy Boundary in 
Terms of Two-Sided 
Significance Level 
First Interim  
Time of Primary PFS 
Analysis 
139 (36%) 
0.0004 
Second Interim 
70% of Overall OS 
Events 
270 (70%) 
0.0146 
Final 
100% of Overall OS 
Events 
385 (100%) 
0.0454 
 
In addition, the DSMC will meet regularly to evaluate patient safety and study conduct for 
the randomized cohorts only. The first such meeting will occur within approximately 90 days 
after the first subject is randomized. Subsequent meetings are described in DSMC section of 
the latest version of the protocol. As a result of these meetings, the DSMC has the authority 
to request additional data and recommend modifications to the study. The DSMC will not 
provide unblinded data to the study team, but may provide aggregate data summaries as 
needed for decision making.  
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6.1.2 
Missing Data 
Every effort will be made to minimize the amount of missing data. However, there will be 
some patients who are either lost to follow-up, withdraw consent from the study, miss certain 
visits, or have other such causes of missing data. Where dates are missing or only partial 
dates are available, the following rules will be used: 
 Missing month, day and year present – if the year part of the date is the same as 
the dosing year, impute the 1st month of dosing, otherwise June will be imputed. 
 Missing day, month and year present – if the year and month are the same as 
dosing year and month, impute the 1st day of dosing, otherwise impute 15. 
 Missing day and month, year present – day and month imputed as June 30. 
 Missing year is not allowed and no imputation of missing year will be used. 
 
For prior and concomitant medication: If the end date is missing or partial, the date will be 
compared as far as possible with the date of first administration of study medication. The 
medication will be assumed to be concomitant, unless there is clear evidence (through 
comparison of partial dates) that it was stopped prior to the first administration of study 
medication.  
For Adverse Events: If the AE onset date is missing or partial, the date will be compared as 
far as possible with the date of first administration of study medication. AEs will be assumed 
to be treatment-emergent, unless there is clear evidence (through comparison of partial dates) 
that the AE started prior to the first administration of study medication.  
6.2 
Standard Summaries and Analyses 
Patient disposition, demographics, baseline characteristics, cancer history, medical history, 
concomitant medications, study drug exposure, and protocol deviation/violation data will be 
summarized using descriptive statistics.  
6.2.1 
Demographics, Baseline Characteristics, and Cancer History 
Demographic and baseline characteristics including height, weight, body surface area (BSA), 
age, gender, cancer history, including HER2 testing (immunohistochemistry [IHC] and/or in 
situ hybridization [ISH] results), Fc receptor polymorphisms, prior chemotherapies, 
surgeries, and radiation received will be summarized. Patients will be excluded from the 
summaries of an individual parameter if data are missing. No statistical comparisons are 
planned as randomization should help to balance these parameters between the two treatment 
groups. 
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Table 4 
Demographics 
Summary 
Population 
Listing and Summary of Patient Disposition 
All patients screened 
Number of Patients Screened, Randomized and Treated by Country/Site 
All patients screened 
Listing and Summary of Protocol Deviations 
ITT 
Listing and Summary of Patient Demographics 
ITT 
Listing and Summary of HER2 Expression by CRF and External Laboratory 
ITT 
Listing and Summary of History of Breast Cancer  
ITT 
Listing and Summary of Estrogen Receptor (ER)/Progesterone Receptor (PgR) 
Status 
ITT 
Listing and Summary of Cancer Disease History Other than Breast Cancer 
ITT 
Listing and Summary of Prior Systemic/Hormonal Therapy, Radiotherapy, 
Surgery for Breast Cancer 
ITT 
Listing and Summary of Prior Systemic Therapy, Radiation, Surgery for Cancer 
Other than Breast Cancer 
ITT 
Listing and Summary of Other (Non cancer) Prior Treatments 
ITT 
Summary of Disease Assessment – Target Lesions at Screening 
ITT 
Summary of Disease Assessment – Non-Target Lesions at Screening 
ITT 
Listing and Summary of Medical History 
ITT 
Listing and Summary of Stratification Factors 
ITT 
 
Infusion sub-study: Above summaries and listings, if applicable, will also be performed for 
patients enrolled and treated in infusion sub-study. 
6.2.2 
Study Drug Exposure 
Summaries using descriptive statistics will be provided for drug exposure for margetuximab 
plus chemotherapy or trastuzumab plus chemotherapy. Exposure will be summarized to 
assess the use of each chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine) in the 
presence and absence of margetuximab or trastuzumab.  
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Table 5 
Summary of Drug Exposure 
Summary 
Population 
Listing of Drug Exposure for Margetuximab 
Safety 
Listing of Drug Exposure for Trastuzumab 
Safety 
Listing of Drug Exposure for Backbone Chemotherapy 
Safety 
Listing and Summary of Patient Withdrawals from Dosing due to Margetuximab or 
Trastuzumab 
Safety 
Listing and Summary of Patient Withdrawals due to Dosing from Backbone 
Chemotherapy 
Safety 
Summary of Number of Cycles of Study Drug - Margetuximab and Trastuzumab 
Safety 
Summary of Number of Cycles of Backbone Chemotherapy Received  
Safety 
Summary of Total Dose of Study Drug Received – Margetuximab and Trastuzumab 
Safety 
Summary of Total Dose Received - Backbone Chemotherapy 
Safety 
Summary of Number of Margetuximab and Trastuzumab Infusions Interrupted or 
Prematurely Terminated 
Safety 
Summary of Dose Intensity for Margetuximab and Trastuzumab  
Safety 
Summary of Dose Intensity for Backbone Chemotherapy 
Safety 
Summary of Number of Backbone Chemotherapies Infusions Interrupted or Prematurely 
Terminated 
Safety 
Summary of Dose Schedule Modifications for Toxicity by Reason - Margetuximab and 
Trastuzumab 
Safety 
Summary of Dose Discontinuations by Reason - Margetuximab and Trastuzumab 
Safety 
Summary of Dose Modifications for Toxicity by Reason – Backbone Chemotherapy 
Safety 
Summary of Dose Discontinuations by Reason – Backbone Chemotherapy 
Safety 
 
Infusion sub-study: Above summaries for drug exposure for margetuximab as well as 
backbone chemotherapies will be also performed for patients enrolled and treated in infusion 
sub-study. 
6.3 
Efficacy Endpoint Analyses 
6.3.1 
Primary Endpoint Analyses 
6.3.1.1 
Progression Free Survival and Overall Survival – Primary 
Analyses 
The same analysis methodology will be used to assess PFS and OS. Survival curves for the 
two treatment groups will be generated using the Kaplan –Meier method. The groups will be 
compared using a stratified log-rank test, stratified by backbone chemotherapy, number of 
metastatic sites, and number of lines of prior therapy in the metastatic setting. The stratified 
log rank test will be carried out with the PROC LIFETEST procedure in SAS® with the 
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Breslow method for handling ties. The following pooling strategy will be employed to handle 
a potential issue of small strata (defined as < 5 events):  
 If there are no small strata, then the stratified log rank test will be performed 
stratified by the original 3 stratification factors.  
 In the case of small strata, one or more stratification factors will be removed, in 
the order of the number of metastatic sites, the number of lines of prior therapy, 
and backbone chemotherapy based on clinical importance, until there are no strata 
with fewer than 5 events under the remaining stratification factors. Then the 
stratified log rank test will be performed stratified by the remaining stratification 
factors.  
 If the procedure for removing stratification factors in the case of small strata 
results in the removal of all 3 stratification factors, then the unstratified log-rank 
test will be performed.  
 
Median PFS and median OS will be estimated using Kaplan-Meier method. The hazard ratio 
for PFS and OS and their 95% CIs will be determined from the stratified Cox proportional 
hazards model with treatment as the only covariate, ties handled by Breslow method, and the 
above pooling strategy applied.  
In order to assess the comparability of follow-up time between the two treatment groups, the 
amount of follow-up in each treatment group will be summarized by the mean number of 
follow-up months as well as the number of patients followed by month of follow-up. 
Table 6 
Primary Endpoint Summaries 
Summary 
Population 
Patient Listing of PFS and OS 
ITT  
Summary of Follow-up Time for PFS and OS 
ITT 
Summary of Stratified PFS  
ITT 
Kaplan-Meier Curves for PFS 
ITT 
Summary of Stratified OS  
ITT 
Kaplan-Meier Curves for OS 
ITT 
Summary of Stratified Cox Proportional Hazards Model for PFS 
ITT 
Summary of Stratified Cox Proportional Hazards Model for OS 
ITT 
Kaplan-Meier Curves for PFS at the Futility Assessment  
ITT (1st 100 events) 
Summary of Conditional Power for PFS at the Futility Assessment 
ITT (1st 100 events) 
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6.3.1.2 
Sensitivity Analyses for Progression Free Survival and 
Overall Survival 
Since these analyses are exploratory, no multiplicity correction will be used. 
6.3.1.2.1 
Sensitivity Analyses for PFS 
1. Unstratified log-rank test as well as the hazard ratio and its 95% CI based on 
unstratified Cox model for PFS analysis with the censoring rules as in Table 1 
will be performed. 
2. The PFS analyses described in Section 6.3.1.1 will be repeated with the censoring 
rules defined in Table 1, except that the documented progression or death will be 
considered a PFS event regardless when it occurs during the study. 
3. The PFS analyses described in Section 6.3.1.1 will be repeated with the censoring 
rules defined in Table 1, except that clinical progression in absence of 
documented tumor progression will be considered a PFS event. The clinical 
progression is a progression based on criteria other than radiographic assessment 
using RECIST v1.1, such as symptom deteriorations or cytology.  
4. The PFS analyses described in Section 6.3.1.1 will be repeated with the censoring 
rules defined in Table 1, with additional censoring at last tumor assessment prior 
to treatment discontinuation for patients who discontinued study treatment due to 
reasons other than documented PD or death. 
 
6.3.1.2.2 
Sensitivity Analyses for OS 
Unstratified log-rank test as well as the hazard ratio estimation and its 95% CI based on 
unstratified Cox model will be performed for OS analysis. 
6.3.1.2.3 
Subgroup Analyses of PFS and OS 
Cox regression including the single covariate of treatment effect will also be used to assess 
the consistency of the treatment effect for a number of subgroups as described below. The 
hazard ratio and 95% confidence interval will be computed and displayed in two forest plots, 
one for PFS and the other for OS. 
The following subgroups for both PFS and OS will be examined: 
 Backbone chemotherapy (capecitabine, gemcitabine, eribulin, vinorelbine) 
 Number of metastatic sites (1-2, >2) 
 Number of lines of prior therapy in the metastatic setting (≤2, >2) 
 Prior use of T-DM1 (yes, no) 
 Region (North America, Europe, Other) 
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 HER2 status (3+ or ISH amplified, Other) 
 Age (≤60, >60) 
 Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0, 1) 
 Race (White, Black, Asian, Other) 
 CD16A (FF, FV, VV) 
 CD32A (HH, HR, RR) 
 CD32B (II, IT, TT) 
 Estrogen receptor (ER) and progesterone receptor (PgR) status (ER+ and/or 
PgR+, ER-and PgR-, Unknown) 
 
6.3.2 
Secondary and Selected Tertiary Endpoint Analyses 
6.3.2.1 
Investigator-Assessed PFS 
The analyses described in Section 6.3.1.1 and Section 6.3.1.2.1 will be performed for 
investigator assessed PFS. The concordance/discordance of progression by investigator 
compared to independent review will be summarized. 
Infusion sub-study: Investigator assessed PFS and OS will also be analyzed for patients 
enrolled and treated in the infusion sub-study. 
6.3.2.2 
Objective Response Rate, Duration of Response, and Clinical 
Benefit Rate 
ORR and CBR, assessed by both independent review and by investigators, will be assessed 
using the best overall response achieved during the study. This response must be confirmed at 
least 28 days after initial response to be considered a confirmed objective response for the 
purpose of calculation of ORR. The two treatment groups will be compared using a Mantel-
Haenszel Chi-Square test stratified by backbone chemotherapy, number of metastatic sites, 
and number of lines of therapy in the metastatic setting. The same pooling strategy as 
described in Section 6.3.1.1 will be applied to handle a potential issue of small strata 
(defined as <5 patients).  
Change from baseline in tumor size over time will be summarized as well as presented by 
spider plots. The best percentage change from baseline will be presented by waterfall plots. 
Change calculations will be based on target lesions measured by independent review as well 
as by investigators.  
DOR curves, assessed by independent review and by investigators, respectively, for the two 
treatment groups will be generated using the Kaplan –Meier method. The groups will be 
compared using a stratified log-rank test.  
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Table 7 
ORR, DOR, and CBR Summaries  
Summary 
Population 
Listing of Investigator Assessed Responses and Independently Assessed 
Responses 
RE 
Summary of Independently Assessed Stratified ORR  
RE 
Summary of Investigator Assessed Stratified ORR   
RE 
Summary of Independently Assessed Stratified CBR  
RE 
Summary of Investigator Assessed Stratified CBR   
RE 
Summary of Investigator Assessed Stratified DOR 
Responders 
Summary of Independently Assessed Stratified DOR 
Responders 
Kaplan Meier Curves for Independently Assessed DOR 
Responders 
Kaplan Meier Curves for Investigator Assessed DOR 
Responders 
Summary of Independently Assessed Responses Compared with Investigator 
Assessed Responses 
RE 
Spider Plots and Summary of Change in Independently Assessed Tumor Size 
Over Time  
Patients with baseline and 
post-baseline target lesion 
measurements 
Spider Plots and Summary of Change in Investigator Assessed Tumor Size Over 
Time  
Patients with baseline and 
post-baseline target lesion 
measurements 
Waterfall Plot of Best Percentage Change from Baseline in Independently 
Assessed Tumor Size 
Patients with baseline and 
post-baseline target lesion 
measurements 
Waterfall Plot of Best Percentage Change from Baseline in Investigator Assessed 
Tumor Size 
Patients with baseline and 
post-baseline target lesion 
measurements 
Listing of Tumor Assessments by Investigators and by Independent Review 
RE 
 
Infusion sub-study: Analyses of ORR, CBR, change from baseline in tumor size over time, 
and DoR based on investigator assessed data will also be performed for patients enrolled and 
treated in the infusion sub-study.  
6.3.2.3 
NFBSI-16 and EQ-5D-5L 
The primary HRQoL endpoint for analysis will be the NFBSI-16 total score. Secondary 
analyses of subscales that add to the total (disease related symptoms, treatment side effects, 
and function/well-being) will also be summarized. 
Change from baseline in NFBSI-16 total score and in EQ-5D-5L utility score will be 
assessed using mixed model repeated measures analysis (MMRM) with treatment group, the 
defined stratification factors, time, and treatment group by time interaction as covariates. 
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Other covariates may be included. Each analysis model will use an unstructured covariance 
matrix. Least square mean estimates at each time point will be presented. 
A Cox proportional hazards model will be used to assess time to symptom progression in 
NFBSI-16 score. Progression will be defined as a ≥ 5-point decrease from baseline in total 
NFBSI-16 score. The same covariates will be used as in the MMRM analyses. 
Reasons for missed visits will be summarized. Graphical methods will be used to assess the 
impact of missed visits. Imputation of missing values will be used for the NFBSI-16. If at 
least half of the items in the scale are answered, any missing items will be assigned the mean 
value of the completed items. 
Table 8 
HRQoL Summaries 
Summary 
Population 
Summary of Reasons for missed Visits – NFBSI-16 and EQ-5D-5L 
ITT 
Summary of NFBSI-16 Mean Scores Overall and by Subscale Across Time 
ITT 
MMRM Results for NFBSI-16 Total Score 
ITT 
Summary of Cox Proportional Hazards Model for Time to Symptom Progression 
ITT 
Kaplan Meier Curves of Time to Symptom Progression 
ITT 
Graph of NFBSI-16 Mean Total Score Across Time 
ITT 
Summary of EQ-5D-5L Mean Scores Overall and by Subscale Across Time 
ITT 
MMRM Results for EQ-5D-5L Total Score 
ITT 
Graphs of EQ-5D-5L Mean Total Score Across Time 
ITT 
 
6.3.3 
Exploratory Analyses 
The effects of margetuximab on PFS and OS as compared to trastuzumab in each allelic 
variation of CD16A, CD32A and CD32B will be evaluated by the estimated hazard ratios 
and 95% CIs as described in Section 6.3.1.2.3. The interaction between each genotype and 
each efficacy endpoint (response, PFS and OS) may be assessed by logistic model for 
response and Cox model for PFS and OS, respectively. 
Infusion sub-study: The analyses of ORR, PFS and OS may be performed in each allelic 
variation of CD16A, CD32A and CD32B if there are enough data to warrant a meaningful 
analysis. 
In addition, exploratory analyses will be performed to evaluate the impact of the subsequent 
use of T-DM1 on the effect of margetuximab on OS. Such analyses may include applying a 
time-dependent Cox model with the treatment as a fixed covariate and the subsequent use of 
T-DM1 as a time-dependent covariate.  
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6.3.4 
Population Pharmacokinetics, Exposure-Response 
Relationships, and Anti-Drug Antibodies 
Serum concentrations of margetuximab will be summarized by study visit using descriptive 
statistics and graphed over time. Population PK modeling will be performed by an external 
vendor. An analysis plan will be created prior to analysis. 
Anti-drug antibodies to margetuximab will categorized as positive or negative and 
summarized using descriptive statistics.  
Table 9 
Summary of PK and Anti-Drug Antibodies - Margetuximab 
Summary 
Population 
Summary of Serum Concentrations of Margetuximab Over Time 
Safety 
Graph of Mean Margetuximab Serum Concentrations Over Time 
Safety 
Summary of Anti-Drug Antibodies to Margetuximab Shift Over Time 
Safety 
 
Infusion sub-study: The above described PK and ADA analyses will also be performed for 
patients enrolled and treated in the infusion sub-study. 
6.4 
Safety Endpoint Analyses 
6.4.1 
Adverse Events 
A number of summary tables of AE will be displayed. Only TEAEs will be summarized in 
tables. The safety population will be used for all AE tables. All AE will be incorporated in the 
listings unless noted otherwise.  
All of these summaries, except the overall table, will display the number and percent of 
patients that experience the given event and will display events by SOC and PT. Events will 
be displayed in alphabetical order of the SOC and in descending order of overall PT 
incidence within each SOC. Tables will include events irrespective of attribution unless 
otherwise indicated.  
A table of overall counts without SOC and preferred terms will include the number of 
patients with: 
 Any AE  
 Any Drug-Related AE 
 Any AE with a CTCAE severity Grade >3  
 Any Drug Related AE with a CTCAE severity grade >3 
 Any Serious AE  
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 Any Drug Related Serious AE 
 Any AE that resulted in study discontinuation 
 Any AE that resulted in study drug discontinuation 
 Any fatal AE 
 Any IRE 
 Any AESI 
 
The following tables will be summarized by SOC and PT: 
 Number of Patients with AE by highest severity 
 Number of Patients with AE by Frequency 
 Number of Patients with ≥Grade 3 AE 
 Number of Patients with Related AE – overall therapy 
 Number of Patients with Related AE by Highest Severity  
 Number of Patients with SAE 
 Number of Patients with Related SAE 
 Number of Patients with AESIs 
 Summary of AE with Incidence Rate ≥5% 
 Summary of Related AE with Incidence Rate ≥5% 
 Summary of AE Leading to Withdrawal of Study Drug 
 Summary of AE Leading to Study Discontinuation 
 Summary of AE that Result in Interruption or Modification of Dosing Schedule 
 Summary of AE that Started During margetuximab or trastuzumab Infusion 
 Summary of AE that Started During Backbone Chemotherapy 
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Table 10 
Adverse Event Summaries 
Summary 
Population 
Overall Summary of Adverse Events 
Safety 
Listing and Summary of Adverse Events  
Safety 
Listing and Summary of ≥Grade 3 Adverse Events  
Safety 
Summary of Related Adverse Events 
Safety 
Summary of ≥Grade 3 Related Adverse Events 
Safety 
Listing and Summary of Serious Adverse Events 
Safety 
Summary of Adverse Events with Incidence Rate >5% 
Safety 
Summary of Related Adverse Events with Incidence Rate >5% 
Safety 
Summary of Related Serious Adverse Events 
Safety 
Summary of Adverse Events Attributed to Margetuximab or Trastuzumab 
Safety 
Summary of Adverse Events Attributed to backbone Chemotherapy 
Safety 
Summary of IREs 
Safety 
Summary of Adverse Events Leading to Withdrawal of Study Drug 
Safety 
Summary of Adverse Events Leading to Discontinuation from the Study 
Safety 
Summary of Adverse Events that Result in Interruption or Modification of Study 
Drug 
Safety 
Summary of Adverse Events that Started During Margetuximab or Trastuzumab 
Infusion 
Safety 
Summary of Adverse Events that Started During Backbone Chemotherapy  
Safety 
Listing and Summary of AESIs – LVEF Dysfunction 
Safety 
Listing and Summary of AESIs – Infusion Related Reactions 
Safety 
Listing and Summary of Deaths 
Safety 
Listing and Summary of Concomitant Medications 
Safety 
Listing and Summary of Concomitant Surgeries 
Safety 
Listing and Summary of Concomitant Radiotherapy 
Safety 
Listing and Summary of Pregnancy Exposure 
Safety 
Summary of ≥Grade 3 IRR by the End of Cycle 2 
Safety 
Listing and Summary of All Grade IRR by Cycle 
Safety 
 
Infusion sub-study: The above AE analyses will also be performed for patients enrolled and 
treated in infusion sub-study. 
6.4.2 
 
Laboratory Values 
Laboratory values will be based on central lab results. The list and timing of collection of 
clinical laboratory parameters are summarized in Appendix 1 Schedule of Events in the latest 
version of the protocol. These parameters will be summarized by mean, median, standard 
deviation/standard error, and range across time points. In cases where an abnormality 
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resulted in a repeat lab test, the repeat value will be used for the summaries. A list of repeated 
labs including original values and repeat values will be included.  
Summary tables will be grouped by parameter type: hematology, serum chemistry, urinalysis, 
and coagulation. Graphs of mean values across study visits will also be generated. Shift 
tables from baseline toxicity grade to worst obtained toxicity grade value may also be 
included. 
Table 11 
Summary of Laboratory Parameters 
Summary 
Population 
Listing and Summary of Laboratory Parameters by Study Visit – Hematology 
Safety 
Listing and Summary of Laboratory Parameters by Study Visit – Serum 
Chemistry 
Safety 
Listing and Summary of Laboratory Parameters by Study Visit – Urinalysis 
Safety 
Listing and Summary of Laboratory Parameters by Study Visit – Coagulation 
Safety 
Shift Table for Hematology Parameters 
Safety 
Shift Table for Coagulation Parameters 
Safety 
Listing of Patients with Treatment-Emergent Laboratory Toxicities ≥ Grade 3 
Safety 
Shift Table for Serum Chemistry Parameters 
Safety 
Listing and Summary of Abnormal Liver Enzymes Meeting Criteria for Hy’s 
Law 
Safety 
Graphs of Mean Hematology Parameters Over Time 
Safety 
Graphs of Mean Serum Chemistry Parameters Over Time 
Safety 
Graphs of Mean Coagulation Parameters Over Time 
Safety 
 
Infusion sub-study: The above laboratory parameters analyses will also be performed for 
patients enrolled and treated in infusion sub-study. 
 
6.4.3 
Electrocardiograms, Multi-Gated Acquisition Scans, Physical 
Examinations, and Vital Signs 
Continuous and categorical ECG data collected as described in Appendix 1 Schedule of 
Events in the latest version of the protocol will be summarized with descriptive statistics in 
tables by study visit. Abnormalities will also be captured as AEs and therefore summarized in 
AE tables.  
As mentioned in Section 5.2.4, newly occurring physical exam abnormalities will be 
captured as AEs and will therefore be summarized in the AE tables. 
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Vital signs (Section 5.2.5) will be summarized by study visit with descriptive statistics. Shift 
tables of baseline toxicity grade value to worst toxicity grade on study value may also be 
included. 
Heart Rate, QTcB, and QTcF will be summarized by visit. QTcF data will be assessed using 
(1) categorical analysis and (2) concentration response analysis. 
Categorical Analysis: 
Frequency distributions of maximum recorded post dose QTcF interval and maximum post 
dose change from baseline QTcF interval (ΔQTcF) will be presented: 
 QTcF: ≤ 450 msec, >450 to 480 msec, >480 to 500 msec, and >500 msec 
 ΔQTcF: ≤ 30 msec, >30 to 60 msec, and >60 msec 
 
Concentration Response Analysis: 
Scatter plot of ΔQTcF versus the nearest corresponding serum margetuximab concentration 
will be presented. The relationship between ΔQTcF versus drug concentration will be 
assessed using a linear mixed effects model (1).  
MUGA scanning or echocardiogram will be presented by change from baseline in LVEF. A 
graph of LVEF change from baseline will also be generated. In addition, time to >15% 
reduction in LVEF value may be summarized using a Kaplan-Meier approach. 
Table 12 
Summary of ECG, Vital Signs, and MUGA Results 
Summary 
Population 
Listing and Summary of Vital Signs Over Time 
Safety 
Listing and Summary QTcF Interval by Study Visit  
Safety 
Listing and Summary of QTcB Interval by Study Visit  
Safety 
Listing and Summary of Heart Rate by Study Visit 
Safety 
Listing and Summary of Categorical Analysis of QTcF 
Safety 
Scatter Plot of Change in QTcF vs. Margetuximab Serum Concentration 
Safety 
Mixed Model Assessing the Relationship Between Change in QTcF and 
Margetuximab Serum Concentrations 
Safety 
Summary of Change in LVEF by Study Visit 
Safety 
Graph of Change in LVEF Over Time 
Safety 
Kaplan-Meier Results for Time to >15% Reduction in LVEF 
Safety 
 
Infusion sub-study: Analyses of above variables will also be performed for patients enrolled 
and treated in infusion sub-study. 
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6.5 
Data Standards 
Clinical Data Interchange Standards Consortium (CDISC) standards will be used. The latest 
version of Study Data Tabulation Model (SDTM) will be used for data tabulations of the 
eCRF data and the latest version of Analysis Dataset Model (ADaM) will be used for the 
analysis datasets. 
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7 
DATA HANDLING CONVENTIONS 
1. Study Day will represent a label in the study summaries defining the study day in 
which a subject assessment is to be conducted. Actual date will be used only where 
required. 
2. Treatment cycle – Treatment cycle will be based on actual infusion dates and may 
differ from the planned cycle.  
3. Study Day 1 – defined as the date of first drug administration following 
randomization. If a partial date exists, it will be imputed as described in 
Section 6.1.2.  
4. Completed Study – Any subject returning for their final study day visit regardless 
of number of doses received or study visits attended. Reasons for non-completion 
will be described. 
5. If there is >1 baseline value for any parameter, baseline will represent the value 
closest, but prior to, first dose. 
6. Weight - If baseline weight is missing, weight from the screening visit will be 
used.  
7. ECG - If baseline ECG is missing, ECG from the screening visit will be used.  
8. If a value is defined as alphanumeric and includes > or ≥, for computation 
purposes the raw value will be increased by one decimal point beyond the 
precision of the value and adding one. For example, >9.0 will be imputed as 9.01. 
9. If a value is defined as alphanumeric and includes < or ≤, for computation 
purposes the raw value will be increased by one decimal point beyond the 
precision of the value and subtracting one. For example, ≤9.0 will be imputed as 
8.99. 
10. Unscheduled visits – in general, unscheduled visits will be listed in patient listings 
but not included in patient summaries.  
 
Additional data conventions or updates to this plan may be needed as blinded data are 
reviewed throughout the study. If so, a Data Convention Document or revised SAP will be 
created and shared with regulatory authorities, as per local requirements, prior to unblinding. 
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8 
REFERENCES 
1. Garnett, C.E., Beasley, Bhattaram, V., Jadhav, P., Madabushi, R., Stockridge, N., 
Tornoe, C., Wang, Y., Zhu, H., Goburru, J. Concentration-QT relationships play a key 
role in the evaluation of proarrhythmic risk during regulatory review. Journal of Clinical 
Pharmacology, V48, p 13-18, 2008. 
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