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

Phase 2

Completed

Conditions: Gastric Cancer
Gastroesophageal Junction Cancer
HER2-positive Gastric Cancer

Interventions: Biological: margetuximab
Biological: Trastuzumab
Biological: Retifanlimab
Other: Chemotherapy
Biological: Tebotelimab

Registration Number: NCT04082364

Lead Sponsor: MacroGenics

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 participants) will evaluate safety and efficacy of margetuximab plus retifanlimab.

Part B Part 1 has 4 arms (50 patients/arm). Participants will be randomized to margetuximab plus retifanlimab plus chemotherapy, margetuximab plus tebotelimab, plus chemotherapy, margetuximab plus chemotherapy, or trastuzumab plus chemotherapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 82

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 participants must have had a disease-free interval of at least 6 months from end of chemo/surgery
2. Participants 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
- Participants 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chemotherapy-free arm	margetuximab	margetuximab plus retifanlimab
Chemotherapy-free arm	Retifanlimab	margetuximab plus retifanlimab
Margetuximab, retifanlimab, and chemotherapy arm	Retifanlimab	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)
Trastuzumab and chemotherapy arm	Chemotherapy	Trastuzumab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)
Margetuximab, retifanlimab, and chemotherapy arm	margetuximab	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)
Margetuximab, retifanlimab, and chemotherapy arm	Chemotherapy	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)
Margetuximab, tebotelimab and chemotherapy arm	margetuximab	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)
Margetuximab, tebotelimab and chemotherapy arm	Tebotelimab	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)
Margetuximab, tebotelimab and chemotherapy arm	Chemotherapy	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)
Margetuximab and chemotherapy arm	margetuximab	margetuximab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)
Margetuximab and chemotherapy arm	Chemotherapy	margetuximab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)
Trastuzumab and chemotherapy arm	Trastuzumab	Trastuzumab plus investigator choice of chemotherapy options. Chemotherapy options: capecitabine and oxaliplatin (XELOX) or modified 5-FU, leucovorin, and oxaliplatin regimen 6 (mFOLFOX-6)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0	Throughout the study, an average of 11 months.	Evaluation of adverse events and serious adverse events (Cohort A)
Objective Response Rate (ORR) for Non-microsatellite Instability-high (Non-MSI-H) Participants (Cohort A) Using Investigator-assessed Radiology Reviews	Throughout the study, an average of 11 months.	Percent of non MSI-H participants with best overall response of complete response (CR) plus partial response (PR) per RECIST 1.1 (Cohorts A ) based on investigator assessment. CR is defined as the disappearance of all target and non-target lesions with no new lesions appearing PR is defined as \>= to a 30% decrease in the sum of the longest dimensions of target lesions, non-progression of non- target lesions, with no new lesions appearing. CR + PR = ORR

Secondary Outcome Measures

Name	Time	Method
Median Progression-free Survival Using Investigator-assessed Radiology Reviews in Cohort A	Throughout the study, an average of 11 months.	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) based on investigator assessment
Median Duration of Response in Cohort A Using Investigator-assessed Radiology Reviews	Throughout the study, an average of 11 months.	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	Throughout the study, an average of 11 months.	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	Throughout the study, an average of 11 months.	Proportion of participants with best overall response of CR plus PR per RECIST 1.1
Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab	Throughout the study, an average of 11 months.
Number of Participants Who Have ADA to Retifanlimab	Throughout the study, an average of 11 months.
Number of Participants Who Have ADA to Tebotelimab	Throughout the study, an average of 11 months.

Trial Locations

Locations (73): Mayo Clinic - Scottsdale
🇺🇸
Scottsdale, Arizona, United States
City of Hope Comprehensive Cancer Center - Duarte
🇺🇸
Duarte, California, United States
Norris Comprehensive Cancer Center (USC)
🇺🇸
Los Angeles, California, United States
Salinas Memorial
🇺🇸
Salinas, California, United States
UCLA School of Medicine
🇺🇸
Santa Monica, California, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Florida Cancer Specialists South
🇺🇸
Fort Myers, Florida, United States
Mayo Clinic - Jacksonville
🇺🇸
Jacksonville, Florida, United States
Ocala Oncology Center PL DBA Florida Cancer Affiliates - Ocala
🇺🇸
Ocala, Florida, United States
Florida Cancer Specialists North
🇺🇸
Saint Petersburg, Florida, United States
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Mayo Clinic - Scottsdale
🇺🇸Scottsdale, Arizona, United States