Gastric Cancer, Gastroesophageal Junction Cancer, HER2-positive Gastric Cancer
Conditions
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.
Interventions
BIOLOGICALmargetuximab
margetuximab: Fc-modified anti-HER2 monoclonal antibody: 15 mg/kg IV, Day1 of each 3-week cycle
BIOLOGICALRetifanlimab
Retifanlimab: anti-PD-1 checkpoint inhibitor 375 mg IV, Day 1 of each 3-week cycle.
BIOLOGICALTebotelimab
Tebotelimab: anti PD-1, anti-LAG3 bispecific DART (R) molecule 600 mg IV, Day 1 of each 3-week cycle.
BIOLOGICALTrastuzumab
Anti-HER2 monoclonal antibody 8 mg/kg loading dose and then 6 mg/kg administered IV on Day 1 of each 3-week cycle
OTHERChemotherapy
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.
Sponsors
Zai Lab (Shanghai) Co., Ltd.
MacroGenics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. | — |
| Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Throughout the study, an average of 11 months. | — |
| 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) |
Countries
China, Germany, Italy, Poland, Singapore, South Korea, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy-free Arm margetuximab: 15 mg/kg IV, Day1 of each 3-week cycle Retifanlimab: 375 mg IV, Day 1 of each 3-week cycle. | 48 |
| Margetuximab, Retifanlimab, and Chemotherapy Arm margetuximab: 15 mg/kg IV, Day1 of each 3-week cycle Retifanlimab: 375 mg IV, Day 1 of each 3-week cycle. Chemotherapy: Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 | 10 |
| Margetuximab, Tebotelimab and Chemotherapy Arm margetuximab: 15 mg/kg IV, Day1 of each 3-week cycle Tebotelimab: 600 mg IV, Day 1 of each 3-week cycle. Chemotherapy: Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 | 6 |
| Margetuximab and Chemotherapy Arm margetuximab: 15 mg/kg IV, Day1 of each 3-week cycle Chemotherapy: Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 | 10 |
| Trastuzumab and Chemotherapy Arm Trastuzumab: 8 mg/kg loading dose and then 6 mg/kg administered IV on Day 1 of each 3-week cycle Chemotherapy: Investigator choice of 1 of 2 chemotherapy regimens: XELOX or mFOLFOX6 | 8 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 23 | 1 | 1 | 2 | 1 |
| Overall Study | Disease progression | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Follow-up terminated by Sponsor | 5 | 0 | 2 | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Margetuximab, Retifanlimab, and Chemotherapy Arm | Margetuximab, Tebotelimab and Chemotherapy Arm | Margetuximab and Chemotherapy Arm | Chemotherapy-free Arm | Trastuzumab and Chemotherapy Arm | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 7.64 | 60.0 years STANDARD_DEVIATION 13.45 | 60.5 years STANDARD_DEVIATION 13.7 | 62.9 years STANDARD_DEVIATION 12.25 | 61.4 years STANDARD_DEVIATION 7.25 | 62.1 years STANDARD_DEVIATION 11.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 6 Participants | 10 Participants | 44 Participants | 8 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 6 Participants | 10 Participants | 21 Participants | 8 Participants | 55 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 23 Participants | 0 Participants | 23 Participants |
| Region of Enrollment China | 8 participants | 5 participants | 9 participants | 0 participants | 7 participants | 29 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Poland | 0 participants | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Singapore | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment South Korea | 0 participants | 0 participants | 0 participants | 19 participants | 0 participants | 19 participants |
| Region of Enrollment Taiwan | 2 participants | 1 participants | 1 participants | 0 participants | 1 participants | 5 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 0 participants | 24 participants | 0 participants | 24 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 1 Participants | 6 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Male | 8 Participants | 2 Participants | 9 Participants | 42 Participants | 7 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 48 | 1 / 9 | 1 / 6 | 2 / 10 | 1 / 8 |
| other Total, other adverse events | 47 / 48 | 9 / 9 | 6 / 6 | 10 / 10 | 7 / 8 |
| serious Total, serious adverse events | 20 / 48 | 4 / 9 | 5 / 6 | 4 / 10 | 2 / 8 |
Outcome results
Primary
Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0
Evaluation of adverse events and serious adverse events (Cohort A)
Time frame: Throughout the study, an average of 11 months.
Population: All patients who receive at least one dose of study drug in Cohort A.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemotherapy-free Arm | Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0 | Any AE | 47 Participants |
| Chemotherapy-free Arm | Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0 | treatment-related AE | 38 Participants |
| Chemotherapy-free Arm | Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0 | severe AE | 25 Participants |
| Chemotherapy-free Arm | Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0 | severe treatment-related AE | 12 Participants |
| Chemotherapy-free Arm | Number of Participants With Adverse Events of Margetuximab Plus Retifanlimab in Cohort A, as Assessed by CTCAE v5.0 | AE resulting in whole study treatment withdrawal | 8 Participants |
Primary
Objective Response Rate (ORR) for Non-microsatellite Instability-high (Non-MSI-H) Participants (Cohort A) Using Investigator-assessed Radiology Reviews
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
Time frame: Throughout the study, an average of 11 months.
Population: All participants in Cohort A who received at least one dose of study treatment and had baseline radiographic tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-free Arm | Objective Response Rate (ORR) for Non-microsatellite Instability-high (Non-MSI-H) Participants (Cohort A) Using Investigator-assessed Radiology Reviews | 52.1 percentage of participants with CR or PR |
Secondary
Disease Control Rate
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)
Time frame: Throughout the study, an average of 11 months.
Population: All participants in Cohort A and B who received at least one dose of study treatment and had baseline radiographic tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-free Arm | Disease Control Rate | 83.3 percent of participants |
| Trastuzumab and Chemotherapy Arm | Disease Control Rate | 87.5 percent of participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Disease Control Rate | 100 percent of participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Disease Control Rate | 100 percent of participants |
| Margetuximab and Chemotherapy Arm | Disease Control Rate | 100 percent of participants |
Secondary
Median Duration of Response in Cohort A Using Investigator-assessed Radiology Reviews
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)
Time frame: Throughout the study, an average of 11 months.
Population: All participants in Cohort A who achieved a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-free Arm | Median Duration of Response in Cohort A Using Investigator-assessed Radiology Reviews | 16.1 months |
Secondary
Median Progression-free Survival Using Investigator-assessed Radiology Reviews in Cohort A
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
Time frame: Throughout the study, an average of 11 months.
Population: All participants who were assigned to treatment in Cohort A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy-free Arm | Median Progression-free Survival Using Investigator-assessed Radiology Reviews in Cohort A | 9.8 months |
Secondary
Number of Participants Who Have ADA to Retifanlimab
Time frame: Throughout the study, an average of 11 months.
Population: Participants in Cohort A and B who received retifanlimab as a component of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Retifanlimab | negative at baseline, negative post baseline | 43 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Retifanlimab | negative at baseline, at least 1 positive post baseline | 3 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Retifanlimab | Positive at baseline, and negative post baseline | 1 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Retifanlimab | not done at baseline, negative post baseline | 1 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have ADA to Retifanlimab | not done at baseline, negative post baseline | 0 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have ADA to Retifanlimab | negative at baseline, negative post baseline | 9 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have ADA to Retifanlimab | Positive at baseline, and negative post baseline | 0 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have ADA to Retifanlimab | negative at baseline, at least 1 positive post baseline | 0 Participants |
Secondary
Number of Participants Who Have ADA to Tebotelimab
Time frame: Throughout the study, an average of 11 months.
Population: Participants who received tebotelimab as a component of study treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Tebotelimab | Negative at baseline, negative post baseline | 1 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Tebotelimab | Negative at baseline, positive at least once post baseline | 4 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have ADA to Tebotelimab | negative at baseline, not done post baseline | 1 Participants |
Secondary
Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab
Time frame: Throughout the study, an average of 11 months.
Population: Participants in Cohort A and B who received margetuximab as a component of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Chemotherapy-free Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Not done at baseline, negative post baseline | 1 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, positive at least once post baseline | 5 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, not done post baseline | 0 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Positive at baseline, as least once positive post baseline | 2 Participants |
| Chemotherapy-free Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | negative at baseline, negative post baseline | 40 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Positive at baseline, as least once positive post baseline | 0 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Not done at baseline, negative post baseline | 0 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, not done post baseline | 0 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, positive at least once post baseline | 1 Participants |
| Trastuzumab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | negative at baseline, negative post baseline | 8 Participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Positive at baseline, as least once positive post baseline | 0 Participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | negative at baseline, negative post baseline | 5 Participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, positive at least once post baseline | 0 Participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Not done at baseline, negative post baseline | 0 Participants |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, not done post baseline | 1 Participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Not done at baseline, negative post baseline | 0 Participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, positive at least once post baseline | 0 Participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | negative at baseline, negative post baseline | 10 Participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Positive at baseline, as least once positive post baseline | 0 Participants |
| Margetuximab, Tebotelimab and Chemotherapy Arm | Number of Participants Who Have Antidrug Antibodies (ADA) to Margetuximab | Negative at baseline, not done post baseline | 0 Participants |
Secondary
ORR for Cohort B
Proportion of participants with best overall response of CR plus PR per RECIST 1.1
Time frame: Throughout the study, an average of 11 months.
Population: All participants in Cohort B who received at least one dose of study treatment and had baseline radiographic tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy-free Arm | ORR for Cohort B | 62.5 percent of participants with CR+PR |
| Trastuzumab and Chemotherapy Arm | ORR for Cohort B | 88.9 percent of participants with CR+PR |
| Margetuximab, Retifanlimab, and Chemotherapy Arm | ORR for Cohort B | 83.3 percent of participants with CR+PR |
| Margetuximab, Tebotelimab and Chemotherapy Arm | ORR for Cohort B | 90.0 percent of participants with CR+PR |