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

• Sponsor: MacroGenics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01828021
• Collaborator: (none)
• Enrollment: 25
• Locations: 6
• Arm: 1
• Actual Duration (Months): 49.4
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: Margetuximab	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Dec 7, 2016
• Actual Study Completion Date: Apr 14, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: margetuximab Monotherapy of Anti-HER2 monoclonal antibody	Biological: Margetuximab; Anti-HER2 monoclonal antibody; Other Names: MGAH22

Outcome Measures

Primary Outcome Measures

1. Best Overall Response [Cycle 2, Day 21]

   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).

Secondary Outcome Measures

1. Response Rate [Day 49]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94115
2	Stanford University	Stanford	California	United States	94305
3	Florida Cancer Research Institute	Plantation	Florida	United States	33324
4	Indiana University	Indianapolis	Indiana	United States	46202
5	Tufts Cancer Center	Boston	Massachusetts	United States	02111
6	Tennessee Oncology	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• MacroGenics

Investigators

• Study Director: Chief Medical Officer, MacroGenics

Study Documents (Full-Text)

None provided.

More Information

Publications

• Nordstrom JL, Gorlatov S, Zhang W, Yang Y, Huang L, Burke S, Li H, Ciccarone V, Zhang T, Stavenhagen J, Koenig S, Stewart SJ, Moore PA, Johnson S, Bonvini E. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi: 10.1186/bcr3069. Epub 2011 Nov 30.

• Responsible Party: MacroGenics
• ClinicalTrials.gov Identifier: NCT01828021
• Other Study ID Numbers: CP-MGAH22-02
• First Posted: Apr 10, 2013
• Last Update Posted: Feb 10, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by MacroGenics: HER2 2+; FISH non-amplified; Relapsed; Refractory; Advanced; Margetuximab; MGAH22
• Additional relevant MeSH terms: Breast Neoplasms; Margetuximab

Study Results

Participant Flow

Recruitment Details	Enrollment occurred at 6 US oncology centers -- 4 academic institutions and 2 clinical research centers, between May 2013 and November 2016.

Arm/Group Title	Margetuximab
Arm/Group Description	Monotherapy of Anti-HER2 monoclonal antibody Margetuximab: Anti-HER2 monoclonal antibody Margetuximab was administered by IV infusion at a dose of 6.0 mg/kg on Days 1, 8, and 15 of each 28-day cycle or or 15 mg/kg every 3 weeks of each 21-day cycle
Period Title: Overall Study
STARTED	25
COMPLETED	0
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Margetuximab
Arm/Group Description	Monotherapy of Anti-HER2 monoclonal antibody Margetuximab: Anti-HER2 monoclonal antibody
Overall Participants	25
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.5 (10.08)
Sex: Female, Male (Count of Participants)
Female	25 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 8%
White	20 80%
More than one race	0 0%
Unknown or Not Reported	1 4%
Region of Enrollment (participants) [Number]
United States	25 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
Performance Status 0	14 56%
Performance Status 1	11 44%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response
Description	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).
Time Frame	Cycle 2, Day 21

Outcome Measure Data

Analysis Population Description

All patients with baseline tumor evaluation, received any amount of study drug, and had a tumor evaluation at Cycle 2 Day 21

Arm/Group Title	Margetuximab
Arm/Group Description	Monotherapy of Anti-HER2 monoclonal antibody Margetuximab: Anti-HER2 monoclonal antibody
Measure Participants	22
Complete Response	0 0%
Partial Response	0 0%
Stable Disease	6 24%
Progressive Disease	12 48%
Not Done	4 16%

2. Secondary Outcome

Title	Response Rate
Description	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.
Time Frame	Day 49

Outcome Measure Data

Analysis Population Description

All patients with baseline tumor measurement, at least one dose of study drug, and Cycle 2 Day 21 tumor assessment

Arm/Group Title	Margetuximab
Arm/Group Description	Monotherapy of Anti-HER2 monoclonal antibody Margetuximab: Anti-HER2 monoclonal antibody
Measure Participants	22
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Adverse events were collected from time of consent until End of Study visit; average time on treatment was 35.6 days
Arm/Group Title	Margetuximab
Arm/Group Description	Monotherapy of Anti-HER2 monoclonal antibody Margetuximab: Anti-HER2 monoclonal antibody
All Cause Mortality
	Margetuximab
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	Margetuximab
	Affected / at Risk (%)	# Events
Total	6/25 (24%)
Cardiac disorders
Supraventricular extrasystoles	1/25 (4%)
Ventricular extrasystoles	1/25 (4%)
Gastrointestinal disorders
Ascites	2/25 (8%)
Diarrhea	1/25 (4%)
Nausea	1/25 (4%)
Pancreatitis	1/25 (4%)
Small intestinal obstruction	1/25 (4%)
Vomiting	1/25 (4%)
Hepatobiliary disorders
Bile duct obstruction	1/25 (4%)
Portal hypertension	1/25 (4%)
Investigations
Alanine aminotransferase increased	1/25 (4%)
Aspartate aminotransferase increased	1/25 (4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges	1/25 (4%)
Renal and urinary disorders
Renal failure acute	2/25 (8%)
Other (Not Including Serious) Adverse Events
	Margetuximab
	Affected / at Risk (%)	# Events
Total	24/25 (96%)
Blood and lymphatic system disorders
Anemia	2/25 (8%)
Gastrointestinal disorders
Nausea	9/25 (36%)
Vomiting	6/25 (24%)
Diarrhea	5/25 (20%)
Abdominal pain	3/25 (12%)
Ascites	2/25 (8%)
General disorders
Fatigue	6/25 (24%)
Chest pain	2/25 (8%)
Chills	2/25 (8%)
Injury, poisoning and procedural complications
Infusion related reaction	5/25 (20%)
Procedural nausea	2/25 (8%)
Investigations
Alanine aminotransferase increased	2/25 (8%)
Aspartate aminotransferase increased	2/25 (8%)
Blood alkaline phosphatase increased	2/25 (8%)
Ejection fraction decreased	2/25 (8%)
Lymphoctye count decreased	2/25 (8%)
Metabolism and nutrition disorders
Decreased appetite	3/25 (12%)
Musculoskeletal and connective tissue disorders
Back pain	2/25 (8%)
Nervous system disorders
Headache	4/25 (16%)
Neuropathy periphera	2/25 (8%)
Psychiatric disorders
Anxiety	2/25 (8%)
Depression	2/25 (8%)
Renal and urinary disorders
Renal failure acute	2/25 (8%)
Respiratory, thoracic and mediastinal disorders
Cough	2/25 (8%)
Dyspnea	2/25 (8%)
Vascular disorders
Hypertension	2/25 (8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.