Combination Margetuximab and Pembrolizumab for Advanced, Metastatic HER2(+) Gastric or Gastroesophageal Junction Cancer

Gastric Cancer Clinical Trial

Official title:

A Phase 1b/2, Open Label, Dose Escalation Study of Margetuximab in Combination With Pembrolizumab in Patients With Relapsed/Refractory Advanced HER2+ Gastroesophageal Junction or Gastric Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02689284
• Other study ID #: CP-MGAH22-05
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2016
• Est. completion date: January 2021

Study information

• Verified date: May 2022
• Source: MacroGenics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This main purpose of this clinical study is to learn about the safety and activity of margetuximab and pembrolizumab combination treatment in patients with HER2+ gastric and gastroesophageal junction cancer.

Description:

Detailed Description: Both margetuximab and pembrolizumab are monoclonal antibodies used in combination to treat HER2+ gastric and gastroesophageal junction cancer. This study has two parts: Dose Escalation and Dose Expansion. The Dose Escalation phase of the study will evaluate safety of escalating doses of the combination treatment. The Dose Expansion phase will evaluate safety and activity of the combination in patients with gastric or gastroesophageal cancer once the final dose and schedule are defined. In addition, a cohort of patients with HER2+ 3+ gastric cancer patients will be enrolled in the Dose Expansion Phase.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 95
• Est. completion date: January 2021
• Est. primary completion date: January 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Signed written informed consent.

2. Age = 18 years old (or minimum age based upon local regulations)

3. Unresectable locally advanced or metastatic histologically proven HER2+ gastroesophageal junction (GEJ) or gastric cancer. Gastric Cancer Expansion Phase will include only gastric cancer patients with 3+ HER2 positivity.

4. HER2+ as 3+ (as defined in AJCC staging manual 8th edition) by IHC or in-situ hybridation (ISH) amplified.

5. Have received prior treatment with trastuzumab.

6. Have received treatment with at least one or more lines of cytotoxic chemotherapy in the metastatic setting.

7. Resolution of chemotherapy, immunotherapy or radiation-related toxicities.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

9. Life expectancy = 12 weeks.

10. Measurable disease as per RECIST 1.1 criteria.

Exclusion Criteria:

1. Patients with symptomatic central nervous system (CNS) metastases.

2. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment.

3. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation.

4. Treatment with any systemic anti-neoplastic therapy, or investigational therapy within the 3 weeks prior to the initiation of study drug.

5. Treatment with radiation therapy within 3 weeks prior to the initiation of study drug administration.

6. Treatment with corticosteroids (=10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days prior to the initiation of study drug administration.

7. History of clinically-significant cardiovascular disease.

8. Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation.

9. History of (non-infectious) pneumonitis that required steroids or presence of active pneumonitis

10. Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.

11. Evidence of active viral, bacterial, or systemic fungal infection.

Related Conditions & MeSH terms

• Esophageal Cancer
• Gastric Cancer
• Stomach Cancer
• Stomach Neoplasms

Intervention

Biological:
• Margetuximab 10 mg/kg
Margetuximab treatment is administered intravenously (IV) once every 21-day cycle
• Margetuximab 15 mg
Margetuximab treatment is administered IV once every 21-day cycle
• Pembrolizumab
Pembrolizumab treatment is administered IV once every 21-day cycle

Locations

Country	Name	City	State
Canada	Juravinski Cancer Centre - McMaster University	Hamilton	Ontario
Canada	McGill University Health Centre	Montreal	Quebec
Korea, Republic of	Kyungbuk National University Hospital	Daegu
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chonbuk National University Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Singapore	National Cancer Centre	Singapore
Singapore	National University Hospital	Singapore
Singapore	Raffles Hospital	Singapore
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Tri-Service General Hospital	Taipei
United States	Johns Hopkins University Medical Center	Baltimore	Maryland
United States	Dana-Farber Cancer Institute/Harvard University Medical Center	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Swedish Cancer Institute	Seattle	Washington
United States	Georgetown University-Lombardi Comprehensive Cancer Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
MacroGenics	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Canada,  Korea, Republic of,  Singapore,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients With Dose Limiting Toxicities	Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab when administered in combination with pembrolizumab	21 days
Primary	Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs).	The number of patients that experience either an AE or a SAE during the study participation	up to 24 months
Primary	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 when administered in combination with pembrolizumab, using conventional Response Evaluation Criteria in Solid Tumors (RECIST) 1.1	12 months
Primary	Number of Patients With a Complete Response (CR) or Partial Response (PR) to Treatment Using irRC Criteria	Investigate the preliminary anti-tumor activity, as measured by objective response rate (ORR) of margetuximab when administered in combination with pembrolizumab, using immune-related response criteria (irRC).	12 Months
Primary	Duration of Response	Duration of response is calculated at the time from CR or PR to relapse or cancer progression.	up to 24 months
Secondary	Overall Survival (OS)	The median length of time between first dose of study medication and death from any cause.	24 Months
Secondary	Progression Free Survival (PFS)	The interval between the first dose of study medication and progression of disease or death from any cause.	24 Months
Secondary	Change From Baseline in Pharmacodynamic Markers in Whole Blood	The planned assessment included examination of markers of T-cell activation	from first dose to the end of treatment, average about 12 months
Secondary	Analysis of HER2 Tumor Cell Membrane Expression in Biopsy Specimens Before and After Treatment		from first dose to the end of treatment, average 12 months.
Secondary	Number of Patients Who Develop Treatment-emergent Anti-drug Antibodies to Margetuximab (Immunogenicity)		Assessed Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Day 1 of every odd cycle, and end of treatment visit, average 12 months
Secondary	Maximum Concentration of Margetuximab at Steady State	Measurement of PK characteristics is limited to margetuximab. No analysis of pembrolizumab was conducted.	At end of infusion on Cycle 1, Day 1. Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months
Secondary	Area Under the Concentration Time Curve at Steady State (AUC ss)	AUC is a mathematical calculation that describes the variation in drug concentration in the blood over time.	Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months
Secondary	Clearance	Drug clearance is the amount of drug removed from the bloodstream by the body per unit of time.	Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit, average 12 months.
Secondary	Volume of Distribution at Steady State	The volume of distribution is related to a whether how much drug is distributed to body tissues, or remains in the bloodstream.	Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit average 12 months .
Secondary	Terminal Half-life	Terminal half-life is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.	Predose and at end of infusion on Cycle 1, Days 1, 2 and 8: Cycle 2, Day 1; Cycle 3, Days 1 and 2; Cycle 5 Day 1, Cycle 7 Day 1, and end of treatment visit average 12 months .