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

Sponsor
MacroGenics (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04082364
Collaborator
Zai Lab (Shanghai) Co., Ltd. (Industry)
82
Enrollment
73
Locations
5
Arms
50
Anticipated Duration (Months)
1.1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
  • Biological: margetuximab
  • Biological: Retifanlimab
  • Biological: Tebotelimab
  • Biological: Trastuzumab
  • Other: Chemotherapy
 Phase 2/Phase 3

Study Design

Study Type:
Interventional
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.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 :
Sep 30, 2019
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Chemotherapy-free arm

margetuximab plus retifanlimab

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

    		•
    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:
  • MGAH22
  • Margenza®

    • Biological: Retifanlimab
    Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.
    Other Names:
  • MGA012
  • INCMGA00012

    • 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.
    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)

    Biological: margetuximab
    margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
    Other Names:
  • MGAH22
  • Margenza®

    • Biological: Tebotelimab
    Tebotelimab: anti PD-1, anti-LAG3 bispecific DART (R) molecule 600 mg IV, Day 1 of each 3-week cycle.
    Other Names:
  • 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.
    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)

    Biological: margetuximab
    margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
    Other Names:
  • MGAH22
  • Margenza®

    • 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.
    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)

    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 Names:
  • 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.

    Outcome Measures

    Primary Outcome Measures

    1. Incidence of Adverse Events of margetuximab plus retifanlimab as assessed by CTCAE v5.0 [Throughout the study up to 24 months]

      Evaluation of adverse events and serious adverse events (Cohort A)

    2. Objective response rate (ORR) for non-microsatellite instability-high (non-MSI-H) patients (Cohort A) [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)

    Secondary Outcome Measures

    1. Progression-free survival [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)

    2. Duration of response [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)

    3. Disease control rate [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)

    4. ORR for Cohort B [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

    5. Number of patients who have antidrug antibodies (ADA) to margetuximab [Throughout study participation, up to 24 months.]

    6. Number of patients who have ADA to retifanlimab [Throughout study participation, up to 24 months.]

    7. Number of patients who have ADA to tebotelimab [Throughout study participation, up to 24 months.]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic - Scottsdale Scottsdale Arizona United States 85259
    2 City of Hope Comprehensive Cancer Center - Duarte Duarte California United States 91010
    3 Norris Comprehensive Cancer Center (USC) Los Angeles California United States 90033
    4 Salinas Memorial Salinas California United States 93901
    5 UCLA School of Medicine Santa Monica California United States 90404
    6 Yale University New Haven Connecticut United States 06511
    7 Florida Cancer Specialists South Fort Myers Florida United States 33901
    8 Mayo Clinic - Jacksonville Jacksonville Florida United States 32224
    9 Ocala Oncology Center PL DBA Florida Cancer Affiliates - Ocala Ocala Florida United States 34474
    10 Florida Cancer Specialists North Saint Petersburg Florida United States 33705
    11 Kaiser Permanente Honolulu Hawaii United States 96814
    12 University of Chicago Chicago Illinois United States 60637
    13 Edward H. Kaplan MD & Associates Skokie Illinois United States 60076
    14 Massachusetts General Hospital Cancer Center Boston Massachusetts United States 02114
    15 Henry Ford Health System Detroit Michigan United States 48202
    16 Cancer & Hematology Centers of Western Michigan - Lemmen-Holton Cancer Pavilion Grand Rapids Michigan United States 49503
    17 Mayo Clinic - Rochester Rochester Minnesota United States 55905
    18 Washington University School of Medicine Saint Louis Missouri United States 63110
    19 Nebraska Heme Onc Lincoln Nebraska United States 68506
    20 Rutgers Cancer Institute of New Jersey New Brunswick New Jersey United States 08903
    21 The University of New Mexico Comprehensive Cancer Center Albuquerque New Mexico United States 87131
    22 Stephenson Cancer Center at OUHSC Oklahoma City Oklahoma United States 73104
    23 Sarah Cannon Research Institute Nashville Tennessee United States 37203
    24 Oncology Consultants Houston Texas United States 77030
    25 Utah Cancer Specialists Salt Lake City Utah United States 84106
    26 Virginia Cancer Specialists Fairfax Virginia United States 22031
    27 Swedish Cancer Institute Seattle Washington United States 98104
    28 University of Wisconsin Madison Wisconsin United States 53792
    29 Beijing Cancer Hospital Beijing China 100142
    30 Jilin Cancer Hospital (Second People's Hospital Of Jilin Province) Changchun China 130000
    31 Fujian Medical University - Fujian Provincial Cancer Hospital (Fujian Provincial Tumor Hospital) Fuzhou China 350005
    32 SIR RUN RUN SHAW Hospital, Zhejiang University school of medicine Hangzhou China 310016
    33 Zhejiang Cancer Hospital Hangzhou China 310022
    34 Affiliated Tumor Hospital of Harbin Medical University- the 3rd Affiliated Hospital of Harbin Harbin China 150081
    35 The First Affiliated Hospital of Anhui Medical University Hefei China 230022
    36 Anhui Provincial Cancer Hospital Hefei China 230031
    37 Jinan Center Hospital Jinan China 250013
    38 Nanjing University Medical School; Nanjing Drug Tower Nanjing China 210000
    39 Zhongshan Hospital Fudan University Shanghai China 200433
    40 Liaoning cancer hospital Shenyang China 110042
    41 Hebei cancer hospital (The Fourth Affiliate) Shijiazhuang China 050000
    42 Wuhan Union Hospital Wuhan China 430022
    43 Henan Cancer Hospital Zhengzhou China 450008
    44 The First Affiliated Hospital of Zhengzhou University Zhenzhou China 450052
    45 Institute of Clinical Cancer Research Krankenhaus Nordwest (IKF) Frankfurt Germany 60488
    46 Haematologisch-Onkologische Praxis Eppendorf Hamburg Germany
    47 Universitätsmedizin Mainz Mainz Germany
    48 Kliniken Maria Hilf GmbH Monchengladbach Germany
    49 Ospedale San Raffaele Milan Italy 20132
    50 Istituto Europeo Di Oncologia Milan Italy
    51 Azienda Ospedaliero-Universitaria Pisana Pisa Italy 56126
    52 Hallym University Sacred Heart Hospital Anyang-Si Korea, Republic of 14068
    53 CHA bundang Gyeonggi-do Korea, Republic of
    54 Inje University Haeundae Paik Hospital Haeundae Korea, Republic of
    55 Seoul National University Bundang Hospital Seongnam-si Korea, Republic of
    56 Asan Medical Center Seoul Korea, Republic of
    57 Korea University Guro Seoul Korea, Republic of
    58 Korea University, Anam Hospital Seoul Korea, Republic of
    59 Samsung Medical Center Seoul Korea, Republic of
    60 Seoul National University Hospital Seoul Korea, Republic of
    61 Yonsei University College of Medicine (Severance Hospital) Seoul Korea, Republic of
    62 Catholic University of Korea St. Vincent Hospital Suwon Korea, Republic of
    63 SPSK nr 1 in Lublin Lublin Poland 20-081
    64 Centrum Medyczne MrukMed Rzeszów Poland 35-922
    65 National University Hospital (Cancer Institute) -Singapore Singapore Singapore 119074
    66 National Cancer Center Singapore Singapore Singapore 169610
    67 Taipei Medical University Hospital Taipei City Taipei Taiwan 110
    68 Kaohsiung Chang Gung MemorialHospital Kaohsiung Taiwan 83301
    69 Chang Gung Memorial Hospital, Keelung Keelung Taiwan 204
    70 Liuying Chi MeiMedical Hospital Tainan city Taiwan 73657
    71 National Taiwan University Taipei Taiwan
    72 Cambridge University Hospitals NHS Foundation Trust Addenbrooke's Hospital Cambridge United Kingdom
    73 The Christie Hospital NHS Foundation Trust Manchester United Kingdom

    Sponsors and Collaborators

    • MacroGenics
    • Zai Lab (Shanghai) Co., Ltd.

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    MacroGenics
    ClinicalTrials.gov Identifier:
    NCT04082364
    Other Study ID Numbers:
    • CP-MGAH22-06
    First Posted:
    Sep 9, 2019
    Last Update Posted:
    Aug 1, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Stomach Neoplasms
    Trastuzumab
    Margetuximab

    Study Results

    No Results Posted as of Aug 1, 2022