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

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

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.

Study Overview

• Status: Completed
• Conditions: Stomach Cancer; Gastric Cancer; Esophageal Cancer
• Intervention / Treatment: Biological: Margetuximab 10 mg/kg; Biological: Pembrolizumab; Biological: Margetuximab 15 mg

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V5C2
      • Juravinski Cancer Centre - McMaster University
  • Quebec
    • Montreal, Quebec, Canada, H4A3J1
      • McGill University Health Centre
• Korea, Republic of
  • Daegu, Korea, Republic of, 41404
    • Kyungbuk National University Hospital
  • Incheon, Korea, Republic of, 21565
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Korea University Guro Hospital
  • Seoul, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 54907
    • Chonbuk National University Hospital
• Singapore
  • Singapore, Singapore
    • National University Hospital
  • Singapore, Singapore
    • National Cancer Centre
  • Singapore, Singapore
    • Raffles Hospital
• Taiwan
  • Taipei, Taiwan
    • Tri-service general hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taipei, Taiwan
    • Taipei Veterans General Hospital
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University-Lombardi Comprehensive Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute/Harvard University Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer 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:

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1: Margetuximab 10 mg/kg plus pembrolizumab 200 mg; margetuximab administered in combination with pembrolizumab	Biological: Margetuximab 10 mg/kg; Margetuximab treatment is administered intravenously (IV) once every 21-day cycle; Other Names: MGAH22; Biological: Pembrolizumab; Pembrolizumab treatment is administered IV once every 21-day cycle; Other Names: MK-3475
EXPERIMENTAL: Cohort 2: Margetuximab 15 mg/kg plus pembrolizumab 200 mg; margetuximab administered in combination with pembrolizumab	Biological: Pembrolizumab; Pembrolizumab treatment is administered IV once every 21-day cycle; Other Names: MK-3475; Biological: Margetuximab 15 mg; Margetuximab treatment is administered IV once every 21-day cycle; Other Names: MGAH22

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	The median length of time between first dose of study medication and death from any cause.	24 Months
Progression Free Survival (PFS)	The interval between the first dose of study medication and progression of disease or death from any cause.	24 Months
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
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.
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
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
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
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.
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 .
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 .

Collaborators and Investigators

• Sponsor: MacroGenics
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Stephen L Eck, M.D., PhD, MacroGenics

Publications and helpful links

General Publications

• Catenacci DVT, Kang YK, Park H, Uronis HE, Lee KW, Ng MCH, Enzinger PC, Park SH, Gold PJ, Lacy J, Hochster HS, Oh SC, Kim YH, Marrone KA, Kelly RJ, Juergens RA, Kim JG, Bendell JC, Alcindor T, Sym SJ, Song EK, Chee CE, Chao Y, Kim S, Lockhart AC, Knutson KL, Yen J, Franovic A, Nordstrom JL, Li D, Wigginton J, Davidson-Moncada JK, Rosales MK, Bang YJ; CP-MGAH22-5 Study Group. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 2020 Aug;21(8):1066-1076. doi: 10.1016/S1470-2045(20)30326-0. Epub 2020 Jul 9.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2016
• Primary Completion (ACTUAL): January 1, 2021
• Study Completion (ACTUAL): January 1, 2021

Study Registration Dates

• First Submitted: January 27, 2016
• First Submitted That Met QC Criteria: February 18, 2016
• First Posted (ESTIMATE): February 23, 2016

Study Record Updates

• Last Update Posted (ACTUAL): August 4, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Pembrolizumab; Antibodies, Monoclonal; Margetuximab
• Other Study ID Numbers: CP-MGAH22-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO