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

A Single Arm, Open-Label, Phase 2 Study of MGAH22 (Fc-optimized Chimeric Anti-HER2 Monoclonal Antibody) in Patients With Relapsed or Refractory Advanced Breast Cancer Whose Tumors Express HER2 at the 2+ Level by Immunohistochemistry and Lack Evidence of HER2 Gene Amplification by FISH

The purpose of this study is to determine if margetuximab is effective in the treatment of certain 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 </= Grade 1 levels or baseline levels and at least 2 weeks must have elapsed before 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 estrogen receptor+ and/or progesterone receptor+ 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