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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: Margetuximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: margetuximab<br>Monotherapy of Anti-HER2 monoclonal antibody | Biological: Margetuximab<br>* Anti-HER2 monoclonal antibody<br>* Other names: MGAH22;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | Response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria based on Cycle 2, Day 21 computed tomography (CT) scans. Response is categorized as complete response (CR): disappearance of all target lesions, confirmed at ≥ 4 weeks; partial response (PR): ≥ 30% decrease in target lesions from baseline, confirmed at ≥ 4 weeks; progressive disease (PD): ≥ 20% increase over smallest sum observed with an absolute increase of at least 5 mm, or appearance of new lesions; and stable disease (SD): neither PR or PD criteria met. A Simon two-stage design was planned in which an initial cohort of 21 patients was treated. If 2 or more responses (PR or CR) are seen at the first tumor re-evaluation on day 21 of Cycle 2, the study would be expanded to include up to 41 patients (20 additional patients in Cohort 2, the second stage of the study) in order to determine whether further development of the drug is warranted (5 or more responses in 41 evaluable patients). | Cycle 2, Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response rate is the proportion of patients achieving a best response of complete response or partial response when such responses are confirmed at least 28 days after initial observation of response. Response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria based on Cycle 2, Day 21 computed tomography (CT) scans. Response is categorized as complete response (CR): disappearance of all target lesions, confirmed at ≥ 4 weeks; partial response (PR): ≥ 30% decrease in target lesions from baseline, confirmed at ≥ 4 weeks; progressive disease (PD): ≥ 20% increase over smallest sum observed with an absolute increase of at least 5 mm, or appearance of new lesions; and stable disease (SD): neither PR or PD criteria met. | Day 49 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 2+, FISH non-amplified, Relapsed, Refractory, Advanced, Margetuximab, MGAH22