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: August 1, 2022
• 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: August 1, 2022
• Actual Study Start Date: September 30, 2019
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 28, 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 and B)

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 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.

• 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. 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

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: December 2023
• Estimated Primary Completion Date: December 2023 (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: July 2022