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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04082364
Recruitment Status : Active, not recruiting
First Posted : September 9, 2019
Last Update Posted : August 1, 2022
Sponsor:
Collaborator:
Zai Lab (Shanghai) Co., Ltd.
Information provided by (Responsible Party):
MacroGenics

Tracking Information
First Submitted Date  ICMJE September 5, 2019
First Posted Date  ICMJE September 9, 2019
Last Update Posted Date August 1, 2022
Actual Study Start Date  ICMJE September 30, 2019
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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)
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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  ICMJE
  • Gastric Cancer
  • Gastroesophageal Junction Cancer
  • HER2-positive Gastric Cancer
Intervention  ICMJE
  • 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  ICMJE
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 28, 2022)
82
Original Estimated Enrollment  ICMJE
 (submitted: September 5, 2019)
850
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China,   Germany,   Italy,   Korea, Republic of,   Poland,   Singapore,   Taiwan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04082364
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Current Responsible Party MacroGenics
Original Responsible Party Same as current
Current Study Sponsor  ICMJE MacroGenics
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Zai Lab (Shanghai) Co., Ltd.
Investigators  ICMJE
Study Director: Stephen L. Eck, MD, PhD MacroGenics
PRS Account MacroGenics
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP