Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer

Study Overview
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Brief Summary
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This is a Phase 2/3, randomized, open-label study for the treatment of patients with HER2-positive Gastric cancer (GC) or Gastroesophageal Junction (GEJ) cancer conducted in two parts. Part A is a single-arm cohort (Cohort A, 40 to 110 patients) will evaluate safety and efficacy of margetuximab plus retifanlimab. Part B has 2 subparts. Cohort B1 has 4 arms (50 patients/arm). Patients will be randomized to margetuximab plus retifanlimab plus chemotherapy, margetuximab plus tebotelimab, plus chemotherapy, margetuximab plus chemotherapy, or trastuzumab plus chemotherapy. The most effective combination with margetuximab from Cohort B1 will be used in Cohort B2. Cohort B2 has 2 arms (250 patients/arm). Patients will be randomized to margetuximab plus retifanlimab or tebotelimab plus chemotherapy, or to trastuzumab plus chemotherapy.

Official Title
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A Phase 2/3 Trial to Evaluate Margetuximab in Combination With INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients With Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer

Conditions
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Gastric Cancer, Gastroesophageal Junction Cancer, HER2-positive Gastric Cancer

Intervention / Treatment
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* Biological: margetuximab
* Biological: Retifanlimab
* Biological: Tebotelimab
* Biological: Trastuzumab
* Other: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma Prior systemic perioperative treatment is allowed; however the patient must have had a disease-free interval of at least 6 months from end of chemo/surgery Patients receiving perioperative anti-HER2 therapy require testing of HER2 status for eligibility Cohort A: HER2-positive (by IHC 3+) and PD-L1-positive (by IHC with 22C3 CPS ≥ 1%) per central review Cohort B: HER2-positive (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. PD -L1 status is not required for enrollment. Availability of formalin-fixed, paraffin-embedded tumor specimen, unstained slides or contemporaneous biopsy for tumor target testing Eastern Cooperative Oncology Group performance status of 0 or 1, verified within 3 days of Day 1 Life expectancy ≥ 6 months At least one radiographically measurable target lesion Acceptable laboratory parameters and adequate organ function Key Exclusion Criteria: Other malignancy that is progressing or required treatment within the past 5 years, with certain exceptions Patients with known MSI-H status History of allogeneic stem cell or tissue/solid organ transplant Central nervous system metastases Clinically significant cardiovascular disease, gastrointestinal disorders, pulmonary compromise Prior neoadjuvant or adjuvant treatment with immunotherapy

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohort A is a single-arm cohort to evaluate safety and efficacy of margetuximab plus retifanlimab. Cohort B Part 1 is a randomized, 4-arm segment to evaluate margetuximab plus retifanlimab plus chemotherapy, margetuximab plus tebotelimab plus chemotherapy, margetuximab plus chemotherapy, vs trastuzumab plus chemotherapy. Cohort B Part 2 is a randomized, 2-arm segment to evaluate margetuximab plus the selected checkpoint inhibitor from Part 1, plus chemotherapy vs. trastuzumab plus chemotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy-free arm<br>margetuximab plus retifanlimab | Biological: margetuximab<br>* margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle<br>* Other names: Margenza®;Biological: Retifanlimab<br>* Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.<br>* Other names: INCMGA00012;|
| Experimental: Margetuximab, retifanlimab, and chemotherapy arm<br>margetuximab plus retifanlimab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6) | Biological: margetuximab<br>* margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle<br>* Other names: Margenza®;Biological: Retifanlimab<br>* Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.<br>* Other names: INCMGA00012;Other: Chemotherapy<br>* Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 Chemotherapy XELOX chemotherapy Capecitabine: 1000 mg/m2 as oral capsules twice a day Days 1-14 of each cycle, Oxaliplatin: 130 mg/m2 of Day 1 of each 3-week cycle as IV infusion mFOLFOX6 chemotherapy: Leucovorin: 400 mg/m2 every 2 weeks as IV infusion, 5-FU bolus: 400 mg/m2 every 2 weeks as IV infusion, 5-FU continuous infusion: 2400 mg/m2 every 2 weeks as a 46 hr infusion, Oxaliplatin: 85 mg/m2 every 2 weeks as IV infusion.<br>|
| Experimental: Margetuximab, tebotelimab and chemotherapy arm<br>margetuximab plus tebotelimab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6) | Biological: margetuximab<br>* margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle<br>* Other names: Margenza®;Biological: Tebotelimab<br>* Tebotelimab: anti PD-1, anti-LAG3 bispecific DART (R) molecule 600 mg IV, Day 1 of each 3-week cycle.<br>* Other names: MGD013;Other: Chemotherapy<br>* Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 Chemotherapy XELOX chemotherapy Capecitabine: 1000 mg/m2 as oral capsules twice a day Days 1-14 of each cycle, Oxaliplatin: 130 mg/m2 of Day 1 of each 3-week cycle as IV infusion mFOLFOX6 chemotherapy: Leucovorin: 400 mg/m2 every 2 weeks as IV infusion, 5-FU bolus: 400 mg/m2 every 2 weeks as IV infusion, 5-FU continuous infusion: 2400 mg/m2 every 2 weeks as a 46 hr infusion, Oxaliplatin: 85 mg/m2 every 2 weeks as IV infusion.<br>|
| Experimental: Margetuximab and chemotherapy arm<br>margetuximab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6) | Biological: margetuximab<br>* margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle<br>* Other names: Margenza®;Other: Chemotherapy<br>* Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 Chemotherapy XELOX chemotherapy Capecitabine: 1000 mg/m2 as oral capsules twice a day Days 1-14 of each cycle, Oxaliplatin: 130 mg/m2 of Day 1 of each 3-week cycle as IV infusion mFOLFOX6 chemotherapy: Leucovorin: 400 mg/m2 every 2 weeks as IV infusion, 5-FU bolus: 400 mg/m2 every 2 weeks as IV infusion, 5-FU continuous infusion: 2400 mg/m2 every 2 weeks as a 46 hr infusion, Oxaliplatin: 85 mg/m2 every 2 weeks as IV infusion.<br>|
| Active Comparator: Trastuzumab and chemotherapy arm<br>Trastuzumab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6) | Biological: Trastuzumab<br>* Anti-HER2 monoclonal antibody 8 mg/kg loading dose and then 6 mg/kg administered IV on Day 1 of each 3-week cycle<br>* Other names: Herceptin;Other: Chemotherapy<br>* Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 Chemotherapy XELOX chemotherapy Capecitabine: 1000 mg/m2 as oral capsules twice a day Days 1-14 of each cycle, Oxaliplatin: 130 mg/m2 of Day 1 of each 3-week cycle as IV infusion mFOLFOX6 chemotherapy: Leucovorin: 400 mg/m2 every 2 weeks as IV infusion, 5-FU bolus: 400 mg/m2 every 2 weeks as IV infusion, 5-FU continuous infusion: 2400 mg/m2 every 2 weeks as a 46 hr infusion, Oxaliplatin: 85 mg/m2 every 2 weeks as IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events of margetuximab plus retifanlimab as assessed by CTCAE v5.0 | Evaluation of adverse events and serious adverse events (Cohort A) | Throughout the study up to 24 months | 
| Objective response rate (ORR) for non-microsatellite instability-high (non-MSI-H) patients (Cohort A) | Proportion of non MSI-H patients with best overall response of complete response (CR) plus partial response (PR) per RECIST 1.1 (Cohorts A ) | Throughout the study up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Time from start of study treatment to the first documented disease progression per RECIST v1.1 or death due to any cause, whichever occurs first. (Cohorts A) | Up to 3 years | 
| Duration of response | Time from the date of initial response (CR or PR) to the date of first documented progression or death from any cause, whichever occurs first (Cohorts A) | Up to 3 years | 
| Disease control rate | Percentage of patients who experienced response of CR, PR or stable disease for at least 3 months from start of study treatment (Cohorts A and B) | Up to 3 years | 
| ORR for Cohort B | Proportion of non-MSI-high patients iwth best overall response of CR plus PR per RECIST 1.1 | Throughout study participation, up to 24 months. | 
| Number of patients who have antidrug antibodies (ADA) to margetuximab |  | Throughout study participation, up to 24 months. | 
| Number of patients who have ADA to retifanlimab |  | Throughout study participation, up to 24 months. | 
| Number of patients who have ADA to tebotelimab |  | Throughout study participation, up to 24 months. |