Safety Study of MGAH22 in HER2-positive Carcinomas

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Gastric Cancer
• Intervention / Treatment: Biological: margetuximab

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: MacroGenics
• Collaborators: National Cancer Institute (NCI); Green Cross Corporation
• Investigators: Study Director: Stephen Eck, MD, MacroGenics

Publications and helpful links

General Publications

• Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nordstrom JL, Li H, Chichili GR, Moore PA, Hong S, Stewart SJ, Baughman JE, Lechleider RJ, Burris HA. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017 Apr 1;28(4):855-861. doi: 10.1093/annonc/mdx002.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): June 14, 2022
• Study Completion (Actual): June 14, 2022

Study Registration Dates

• First Submitted: June 17, 2010
• First Submitted That Met QC Criteria: June 21, 2010
• First Posted (Estimate): June 22, 2010

Study Record Updates

• Last Update Posted (Actual): October 19, 2022
• Last Update Submitted That Met QC Criteria: October 18, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Margetuximab
• Other Study ID Numbers: CP-MGAH22-01; 02598-10 (Other Grant/Funding Number: NCI CRADA)