Phase 2 Study of the Monoclonal Antibody MGAH22 (Margetuximab) in Patients With Relapsed or Refractory Advanced Breast Cancer

In the pivotal study that established that Herceptin® was highly effective when added to
standard chemotherapy in the front-line treatment of women with HER2 positive metastatic
breast cancer, benefit appeared to accrue to those patients whose tumors expressed the HER2
oncoprotein at the 3+ level by immunohistochemistry (IHC) or those patients whose tumors
demonstrated evidence of HER2 gene amplification by fluorescence in situ hybridization (FISH)
testing. Similarly, when Herceptin® was used as a single therapy in women with metastatic
breast cancer that had progressed following cytotoxic chemotherapy, 3+ overexpression of
HER2, but not 2+ expression, was associated with response to treatment. These and other
studies have led to the recommendation that Herceptin® should be administered to patients
with breast cancer whose tumors exhibit 3+ overexpression or gene amplification. This study
will evaluate whether treatment of patients with tumors that would not be expected to respond
to Herceptin® therapy, namely those that lack HER2 gene amplification and express the
oncoprotein at the 2+ level by IHC, may benefit from the use of the anti-HER2 monoclonal
antibody, MGAH22. If 5 or more responses are seen in 41 evaluable patients, then further
clinical development of margetuximab will be justified.

Inclusion Criteria:

- Histologically or cytologically confirmed invasive carcinoma of the breast

- Treatment with at least two prior systemic therapies for advanced (unresectable
locoregional or metastatic) disease

- Evidence of HER2 oncoprotein expression at the 2+ level by central laboratory.
Patients whose tumors exhibit 2+ staining by IHC are eligible for the study.

- Patients whose tumors score 1+ by conventional IHC, are non-amplified by FISH testing,
and whose tumors score > or = 10.5 by HERmark® testing, are eligible for the study.

- Evidence of lack of HER2 oncogene amplification as determined by FISH testing by
central laboratory

- Performance Status of 0 or 1

- Life expectancy at least 6 months

- Measurable disease (by RECIST 1.1)

- Acceptable laboratory parameters and organ reserve

- Baseline left ventricular ejection fraction > or = 50%

- Anti-cancer therapy (including conventional cytotoxic chemotherapy and/or biological
therapy) and radiotherapy must be completed and any associated toxicities resolved to
enrollment. Treatment with monoclonal antibodies must be completed at least 14 days
before entry. Must have completed immunosuppressive medications or vaccinations before
enrollment.

- Patients who are ER+ and/or PR+ and who are receiving anti-hormone therapy for at
least three months may continue to receive such therapy during the course of the trial

- Eighteen (18) years of age or older

Exclusion Criteria:

- Major surgery or trauma within 4 weeks

- Known hypersensitivity to murine or recombinant proteins, polysorbate 80, or any
excipient contained in the margetuximab drug formulation

- Second primary malignancy that has not been in remission for more than 3 years

- History of active viral, bacterial, or systemic fungal infection requiring parenteral
treatment within 14 days

- History within 3 months of deep vein thrombosis, pulmonary embolism, or stroke

- Symptomatic or untreated central nervous system (CNS) metastatic disease. Patients
with previously treated CNS metastatic disease which has been stable for at least 56
days are eligible

- Requirement, at time of study entry, for concurrent steroids > 10 mg/day of oral
prednisone or the equivalent, except steroid inhaler, nasal spray, or ophthalmic
solution

- Serious medical condition that would impair the ability to receive or tolerate
margetuximab; dementia or altered mental status that would preclude provision of
informed consent

- Uncontrolled hypertension, heart disease including history of congestive heart
failure, history of myocardial infarction, angina pectoris requiring medication,
clinically significant valvular heart disease, high risk arrhythmias, or disease
corresponding to New York Heart Association class III or IV.

- Significant pulmonary compromise

- Have previously been exposed to MGAH22 in this or any other trial