Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer (MAHOGANY)
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| ClinicalTrials.gov Identifier: NCT04082364 |
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Recruitment Status :
Active, not recruiting
First Posted : September 9, 2019
Last Update Posted : December 26, 2023
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Gastric Cancer Gastroesophageal Junction Cancer HER2-positive Gastric Cancer | Biological: margetuximab Biological: Retifanlimab Biological: Tebotelimab Biological: Trastuzumab Other: Chemotherapy | Phase 2 Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 82 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention 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) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Actual Study Start Date : | September 30, 2019 |
| Estimated Primary Completion Date : | March 2024 |
| Estimated Study Completion Date : | March 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Chemotherapy-free arm
margetuximab plus retifanlimab
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Biological: margetuximab
margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
Other Names:
Biological: Retifanlimab Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.
Other Names:
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Experimental: Margetuximab, retifanlimab, and chemotherapy arm
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
margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
Other Names:
Biological: Retifanlimab Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.
Other Names:
Other: Chemotherapy 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. |
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Experimental: Margetuximab, tebotelimab and chemotherapy arm
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)
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Biological: margetuximab
margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
Other Names:
Biological: Tebotelimab Tebotelimab: anti PD-1, anti-LAG3 bispecific DART (R) molecule 600 mg IV, Day 1 of each 3-week cycle.
Other Name: MGD013 Other: Chemotherapy 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. |
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Experimental: Margetuximab and chemotherapy arm
margetuximab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)
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Biological: margetuximab
margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
Other Names:
Other: Chemotherapy 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. |
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Active Comparator: Trastuzumab and chemotherapy arm
Trastuzumab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)
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Biological: Trastuzumab
Anti-HER2 monoclonal antibody 8 mg/kg loading dose and then 6 mg/kg administered IV on Day 1 of each 3-week cycle
Other Name: Herceptin Other: Chemotherapy 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. |
- Incidence of Adverse Events of margetuximab plus retifanlimab as assessed by CTCAE v5.0 [ Time Frame: Throughout the study up to 24 months ]Evaluation of adverse events and serious adverse events (Cohort A)
- Objective response rate (ORR) for non-microsatellite instability-high (non-MSI-H) patients (Cohort A) [ Time Frame: Throughout the study up to 24 months ]Proportion of non MSI-H patients with best overall response of complete response (CR) plus partial response (PR) per RECIST 1.1 (Cohorts A )
- Progression-free survival [ Time Frame: Up to 3 years ]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)
- Duration of response [ Time Frame: Up to 3 years ]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)
- Disease control rate [ Time Frame: Up to 3 years ]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)
- ORR for Cohort B [ Time Frame: Throughout study participation, up to 24 months. ]Proportion of non-MSI-high patients iwth best overall response of CR plus PR per RECIST 1.1
- Number of patients who have antidrug antibodies (ADA) to margetuximab [ Time Frame: Throughout study participation, up to 24 months. ]
- Number of patients who have ADA to retifanlimab [ Time Frame: Throughout study participation, up to 24 months. ]
- Number of patients who have ADA to tebotelimab [ Time Frame: Throughout study participation, up to 24 months. ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Key Inclusion Criteria:
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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:
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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
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Clinically significant cardiovascular disease, gastrointestinal disorders, pulmonary compromise
- Prior neoadjuvant or adjuvant treatment with immunotherapy
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): NCT04082364
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| Study Director: | Stephen L. Eck, MD, PhD | MacroGenics |
| Responsible Party: | MacroGenics |
| ClinicalTrials.gov Identifier: | NCT04082364 |
| Other Study ID Numbers: |
CP-MGAH22-06 |
| First Posted: | September 9, 2019 Key Record Dates |
| Last Update Posted: | December 26, 2023 |
| Last Verified: | December 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Stomach Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Digestive System Diseases |
Gastrointestinal Diseases Stomach Diseases Trastuzumab Margetuximab Antineoplastic Agents, Immunological Antineoplastic Agents |