Safety Study of MGAH22 in HER2-positive Carcinomas

Study Overview
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Brief Summary
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The purpose of this study is to determine if MGAH22 is safe when given by intravenous (IV) infusion to patients with HER2-positive cancer. The study will also evaluate how long MGAH22 stays in the blood and how long it takes for it to leave the body, what is the highest dose that can safely be given, and whether it has an effect on tumors.

Official Title
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A Phase 1, Dose Escalation Study of MGAH22 in Patients With Refractory HER2 Positive Breast Cancer and Patients With Other HER2 Positive Carcinomas for Whom No Standard Therapy Is Available

Conditions
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Breast Cancer, Gastric 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 carcinoma that overexpresses HER2 by immunohistochemistry (2+ or 3+ positivity by HercepTest or equivalent). Progressive disease during or after last treatment regimen. Appropriate treatment history for histological entity. ECOG Performance Status <= 1. Life expectancy >= 3 month. Measurable disease Acceptable laboratory parameters and adequate organ reserve. Baseline LVEF >50% Exclusion Criteria: Lifetime anthracycline exposure > 350 mg/m2 of doxorubicin or equivalent Major surgery within four weeks before enrollment. Known hypersensitivity to murine or recombinant proteins, polysorbate 80, or any excipient contained in the drug formulation. Second primary malignancy that has not been in remission for greater than 3 years. Treated non-melanoma skin cancer, cervical carcinoma in situ on biopsy, or squamous intraepithelial lesion on PAP smear, localized prostate cancer (Gleason score < 6), or resected melanoma in situ are exceptions and do not require a 3 year remission. Active viral, bacterial, or systemic fungal infection requiring parenteral treatment within four weeks of enrollment. Patients requiring any oral antiviral, fungal, or bacterial therapy must have completed treatment within one week of enrollment. History of chronic or recurrent infections that require continual use of antiviral, antifungal, or antibacterial agents. History of deep vein thrombosis, pulmonary embolism, myocardial infarction, or stroke within three months of enrollment. Known history of central nervous system (CNS) metastatic disease with evidence of residual or recurrent disease upon entry. New York Heart Association class III or IV heart disease.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: 0.1 mg/kg weekly for 4 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 2: 0.3 mg/kg weekly for 4 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 3: 1.0 mg/kg weekly for 4 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 4: 3.0 mg/kg weekly for 4 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 5: 6.0 mg/kg weekly for 4 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 6: 10 mg/kg weekly every 3 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 7: 15 mg/kg weekly every 3 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|
| Experimental: Cohort 8: 18 mg/kg weekly every 3 weeks<br>Anti-HER2 monoclonal antibody (margetuximab) | Biological: margetuximab<br>* margetuximab<br>* Other names: MGAH22;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events and Serious Adverse Events | Note that serious adverse events that are considered study drug related can be reported at any time after Study Day 50 or 28 days after the last infusion. | Up to 28 days after last infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities for weekly dosing | Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab | up to Study Day 28 for weekly dosing | 
| Number of participants with dose limiting toxicities every 3-week dosing | Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab | Up to Study Day 21 day for every 3-week dosing | 
| Concentration of Margetuximab at Steady State once-weekly doses of margetuximab |  | Study Day 1, 2, 4, 5, 8, 15, 22, 29 ,36, 50, every 4 weeks thereafter throughout study completion, average 2 months. | 
| Number of patients who develop treatment-emergent anti-drug antibodies to margetuximab (Immunogenicity) |  | Study Day 1, 22, 50, every 4 weeks thereafter throughout study completion, average 2 months. | 
| Maximum Concentration of Margetuximab at Steady State once every 3 weeks schedule |  | Study Day 1, 2, 4, 5, 22, 29 ,36, 50, every 3 weeks thereafter throughout study completion, average 10 months. | 
| Area Under the Concentration Time Curve at Steady State (AUC ss) once every 3 weeks schedule | AUC is a mathematical calculation that describes the drug concentration in the blood over time. | Study Day 1 through Day 22 | 
| Area Under the Concentration Time Curve at Steady State (AUC ss) weekly dosing schedule | AUC is a mathematical calculation that describes the drug concentration in the blood over time. | Study Day 1 through Day 8 | 
| Clearance once every 3 weeks schedule | Drug clearance is the amount of drug removed from the bloodstream per unit of time. | Study Day 1, 2, 4, 5, 22, 29 ,36, 50, every 3 weeks thereafter through study completion, average 10 months | 
| Volume of Distribution at Steady State once every 3 weeks | The volume of distribution is related to a whether how much drug is distributed to body tissues or remains in the bloodstream | Study Day 1, 2, 4, 5, 22, 29 ,36, 50, every 3 weeks thereafter through study completion, average 10 months | 
| Terminal Half-life once every 3 weeks schedule | Terminal half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium. | Study Day 1 through Day 22 | 
| Terminal Half-life once every weekly dosing schedule | Terminal half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium. | Study Day 1 through Day 8 | 
| Number of Patients Who Develop Treatment-emergent Anti-drug Antibodies to Margetuximab once every 3 weeks schedule |  | Study Day 1, 2, 4, 5, 22, 29 ,36, 50, every 3 weeks thereafter through study completion, average 10 months | 
| Number of Patients with a Complete Response (CR) or Partial Response (PR) to Treatment | Investigate the preliminary anti-tumor activity as measured by response to treatment of margetuximab, using conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Assessed at 6, 18, 30, 42, and 54 weeks, they every 24 weeks until treatment discontinuation, average 10 months | 
| Duration of response | Duration of response is calculated at the time from CR or PR to relapse or cancer progression | Assessed at 6, 18, 30, 42, and 54 weeks, they every 24 weeks until treatment discontinuation,average 10 months | 
| Progression free survival | The interval between the first dose of study medication and progression of disease or death from any cause | Assessed at 6, 18, 30, 42, and 54 weeks, they every 24 weeks until treatment discontinuation, average 10 months | 
| Number of patients with complete response, partial response, stable disease, or progressive disease according to each CD16A-158 genotype (FF, FV, VV) | Fc Receptor polymorphisms may affect responsiveness to immunotherapies | Fc receptor genotypes assessed prior to study treatment. Response to treatment assessed at 6, 18, 30, 42, and 54 weeks, then every 24 weeks until treatment discontinuation, average 10 months | 
| Changes in immune cell subsets | Changes in immune cell subsets may affect responsiveness to immunotherapies | Before infusion and 1 hour after infusion on Study Day 1, Study Day 2, before infusion on Study Day 22 and 50 | 
| Serum cytokines in the blood | Changes in the levels of cytokines in the blood may be related to an immune response to treatment. | Study Day 1, 2, 4, 5, 22, 29 ,36, 50, every 3 weeks thereafter through study completion, average 10 months | 
| Amount HER2 in the blood | Levels of HER2 in the bloodstream may indicate response to treatment. | Before infusion and 1 hour after infusion on Study Day 1, Study Day 2, before infusion on Study Day 22 and 50 | 
| Antibody dependent cellular cytotoxicity (ADCC) activity | ADCC activity is the ability of immune cells (like lymphocytes) to kill cells that have immune markers (like HER2) on the cell surface | Before infusion and 1 hour after infusion on Study Day 1, Study Day 2, before infusion on Study Day 22 and 50 | 
| Fc receptor occupancy | Fc receptor occupancy is the amount of time that the receptor is bound to an immune marker (like HER2) on the cell surface. | Before infusion and 1 hour after infusion on Study Day 1, Study Day 2, before infusion on Study Day 22 and 50 |