Safety Study of MGAH22 in HER2-positive Carcinomas

• ClinicalTrials.gov Identifier: NCT01148849
• Recruitment Status: Completed
• First Posted: June 22, 2010
• Last Update Posted: October 19, 2022
• Sponsor: MacroGenics
• Collaborators: Green Cross Corporation; National Cancer Institute (NCI)
• Information provided by (Responsible Party): MacroGenics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Gastric Cancer	Biological: margetuximab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 66 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2010
• Actual Primary Completion Date: June 14, 2022
• Actual Study Completion Date: June 14, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Occurrence of Adverse Events and Serious Adverse Events [ Time Frame: Up to 28 days after last infusion ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Maryland

National Cancer Institute

Bethesda, Maryland, United States, 20892

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

Korea, Republic of

Seoul National University Hospital

Seoul, Korea, Republic of, 110-744

Sponsors and Collaborators

MacroGenics

Green Cross Corporation

National Cancer Institute (NCI)

Investigators

• Study Director: Stephen Eck, MD; MacroGenics

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: MacroGenics
• ClinicalTrials.gov Identifier: NCT01148849
• Obsolete Identifiers: NCT01195935
• Other Study ID Numbers: CP-MGAH22-01; 02598-10 ( Other Grant/Funding Number: NCI CRADA )
• First Posted: June 22, 2010
• Last Update Posted: October 19, 2022
• Last Verified: July 2022

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Margetuximab; Antineoplastic Agents