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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02689284
Recruitment Status : Completed
First Posted : February 23, 2016
Results First Posted : August 4, 2022
Last Update Posted : August 4, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
MacroGenics

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Gastric Cancer Stomach Cancer Esophageal Cancer Biological: Margetuximab 10 mg/kg Biological: Margetuximab 15 mg Biological: Pembrolizumab Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 95 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 2016
Actual Primary Completion Date : January 2021
Actual Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: MGAH22

Biological: Pembrolizumab
Pembrolizumab treatment is administered IV once every 21-day cycle
Other Name: MK-3475
Experimental: Cohort 2: Margetuximab 15 mg/kg plus pembrolizumab 200 mg
margetuximab administered in combination with pembrolizumab
 Biological: Margetuximab 15 mg
Margetuximab treatment is administered IV once every 21-day cycle
Other Name: MGAH22

Biological: Pembrolizumab
Pembrolizumab treatment is administered IV once every 21-day cycle
Other Name: MK-3475


Outcome Measures
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Primary Outcome Measures :
  1. Number of Patients With Dose Limiting Toxicities [ Time Frame: 21 days ]
    Characterize maximum tolerated dose (MTD) or maximum administered dose (MAD) (if no MTD is defined) of margetuximab when administered in combination with pembrolizumab

  2. Number of Patients With Adverse Events (AEs) and Serious Adverse Events (SAEs). [ Time Frame: up to 24 months ]
    The number of patients that experience either an AE or a SAE during the study participation

  3. Number of Patients With a Complete Response (CR) or Partial Response (PR) to Treatment [ Time Frame: 12 months ]
    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

  4. Number of Patients With a Complete Response (CR) or Partial Response (PR) to Treatment Using irRC Criteria [ Time Frame: 12 Months ]
    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).

  5. Duration of Response [ Time Frame: up to 24 months ]
    Duration of response is calculated at the time from CR or PR to relapse or cancer progression.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 24 Months ]
    The median length of time between first dose of study medication and death from any cause.

  2. Progression Free Survival (PFS) [ Time Frame: 24 Months ]
    The interval between the first dose of study medication and progression of disease or death from any cause.

  3. Change From Baseline in Pharmacodynamic Markers in Whole Blood [ Time Frame: from first dose to the end of treatment, average about 12 months ]
    The planned assessment included examination of markers of T-cell activation

  4. Analysis of HER2 Tumor Cell Membrane Expression in Biopsy Specimens Before and After Treatment [ Time Frame: from first dose to the end of treatment, average 12 months. ]
  5. Number of Patients Who Develop Treatment-emergent Anti-drug Antibodies to Margetuximab (Immunogenicity) [ Time Frame: 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 ]
  6. Maximum Concentration of Margetuximab at Steady State [ Time Frame: 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 ]
    Measurement of PK characteristics is limited to margetuximab. No analysis of pembrolizumab was conducted.

  7. Area Under the Concentration Time Curve at Steady State (AUC ss) [ Time Frame: 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 ]
    AUC is a mathematical calculation that describes the variation in drug concentration in the blood over time.

  8. Clearance [ Time Frame: 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. ]
    Drug clearance is the amount of drug removed from the bloodstream by the body per unit of time.

  9. Volume of Distribution at Steady State [ Time Frame: 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 . ]
    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 [ Time Frame: 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 is the time required to divide the plasma concentration by two after reaching pseudo-equilibrium.


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

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02689284


Locations
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Sponsors and Collaborators
MacroGenics
Merck Sharp & Dohme LLC
Investigators
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Study Director: Stephen L Eck, M.D., PhD MacroGenics
  Study Documents (Full-Text)

Documents provided by MacroGenics:
Study Protocol  [PDF] June 29, 2020
Statistical Analysis Plan  [PDF] December 17, 2020

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

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Responsible Party: MacroGenics
ClinicalTrials.gov Identifier: NCT02689284    
Other Study ID Numbers: CP-MGAH22-05
First Posted: February 23, 2016    Key Record Dates
Results First Posted: August 4, 2022
Last Update Posted: August 4, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Pembrolizumab
 Margetuximab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs