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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Gastric Cancer, Stomach Cancer, Esophageal Cancer

Intervention / Treatment
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* Biological: Margetuximab 10 mg/kg
* Biological: Margetuximab 15 mg
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent. Age ≥ 18 years old (or minimum age based upon local regulations) 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. HER2+ as 3+ (as defined in AJCC staging manual 8th edition) by IHC or in-situ hybridation (ISH) amplified. Have received prior treatment with trastuzumab. Have received treatment with at least one or more lines of cytotoxic chemotherapy in the metastatic setting. Resolution of chemotherapy, immunotherapy or radiation-related toxicities. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy ≥ 12 weeks. Measurable disease as per RECIST 1.1 criteria. Exclusion Criteria: Patients with symptomatic central nervous system (CNS) metastases. Patients with any history of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment. History of prior allogeneic bone marrow, stem-cell or solid organ transplantation. Treatment with any systemic anti-neoplastic therapy, or investigational therapy within the 3 weeks prior to the initiation of study drug. Treatment with radiation therapy within 3 weeks prior to the initiation of study drug administration. 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. History of clinically-significant cardiovascular disease. Clinically-significant pulmonary compromise, including a requirement for supplemental oxygen use to maintain adequate oxygenation. History of (non-infectious) pneumonitis that required steroids or presence of active pneumonitis Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis. Evidence of active viral, bacterial, or systemic fungal infection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 . |