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

• ClinicalTrials.gov Identifier: NCT04082364
• Recruitment Status: Active, not recruiting
• First Posted: September 9, 2019
• Last Update Posted: May 16, 2024
• Sponsor: MacroGenics
• Collaborator: Zai Lab (Shanghai) Co., Ltd.
• Information provided by (Responsible Party): MacroGenics

Tracking Information

• First Submitted Date: September 5, 2019
• First Posted Date: September 9, 2019
• Last Update Posted Date: May 16, 2024
• Actual Study Start Date: September 30, 2019
• Actual Primary Completion Date: January 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2022)

• 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 )

Original Primary Outcome Measures (submitted: September 5, 2019)

• Incidence of Adverse Events of margetuximab plus INCMGA00012 as assessed by CTCAE v5.0 [ Time Frame: 6 month intervals ]
  Evaluation of adverse events and serious adverse events (Cohort A)
• Objective response rate (ORR) [ Time Frame: 3 years ]
  Proportion of patients with best overall response of complete response (CR) plus partial response (PR) per RECIST 1.1 (Cohorts A and B)
• Overall survival [ Time Frame: Up to 3 years ]
  Time from randomization to death from any cause (Cohort B)

Current Secondary Outcome Measures (submitted: July 28, 2022)

• 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. ]

Original Secondary Outcome Measures (submitted: September 5, 2019)

• 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 and B)
• 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 and B)
• 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)
• Patient reported quality of life [ Time Frame: Up to 3 years ]
  Quality of life as assessed using the Functional Assessment of Cancer Therapy - Gastric Questionnaire (FACT-Ga) (Cohort B)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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 Part 1 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Gastric Cancer
• Gastroesophageal Junction Cancer
• HER2-positive Gastric Cancer

Intervention

• Biological: margetuximab
  margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
  Other Names:

  • MGAH22
  • Margenza®
• Biological: Retifanlimab
  Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.
  Other Names:

  • MGA012
  • INCMGA00012
• 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
• 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.

Study Arms

• Experimental: Chemotherapy-free arm
  margetuximab plus retifanlimab
  Interventions:

  • Biological: margetuximab
  • Biological: Retifanlimab
• 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)

  Interventions:

  • Biological: margetuximab
  • Biological: Retifanlimab
  • Other: Chemotherapy
• 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)
  Interventions:

  • Biological: margetuximab
  • Biological: Tebotelimab
  • Other: Chemotherapy
• 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)
  Interventions:

  • Biological: margetuximab
  • Other: Chemotherapy
• 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)
  Interventions:

  • Biological: Trastuzumab
  • Other: Chemotherapy

• Publications *: Catenacci DV, Rosales M, Chung HC, H Yoon H, Shen L, Moehler M, Kang YK. MAHOGANY: margetuximab combination in HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 2021 Apr;17(10):1155-1164. doi: 10.2217/fon-2020-1007. Epub 2020 Dec 2.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 28, 2022): 82
• Original Estimated Enrollment (submitted: September 5, 2019): 850
• Estimated Study Completion Date: June 2025
• Actual Primary Completion Date: January 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma

  1. 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
  2. Patients receiving perioperative anti-HER2 therapy require testing of HER2 status for eligibility
  3. Cohort A: HER2-positive (by IHC 3+) and PD-L1-positive (by IHC with 22C3 CPS ≥ 1%) per central review
  4. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, Germany, Italy, Korea, Republic of, Poland, Singapore, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04082364
• Other Study ID Numbers: CP-MGAH22-06
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: MacroGenics
• Original Responsible Party: Same as current
• Current Study Sponsor: MacroGenics
• Original Study Sponsor: Same as current
• Collaborators: Zai Lab (Shanghai) Co., Ltd.

Investigators

• Study Director: Stephen L. Eck, MD, PhD; MacroGenics

• PRS Account: MacroGenics
• Verification Date: May 2024