Efficacy Study of Nivolumab Plus Ipilimumab or Nivolumab Plus Chemotherapy Against Chemotherapy in Stomach Cancer or Stomach/Esophagus Junction Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to compare how long patients with gastric or gastroesophageal junction cancer live after receiving nivolumab and ipilimumab or nivolumab and chemotherapy compared with patients receiving chemotherapy alone.

Official Title
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A Randomized, Multicenter, Open-Label, Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab in Combination With Oxaliplatin Plus Fluoropyrimidine Versus Oxaliplatin Plus Fluoropyrimidine in Subjects With Previously Untreated Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

Conditions
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Gastric Cancer, Gastroesophageal Junction Cancer, Esophageal Adenocarcinoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Oxaliplatin
* Drug: Capecitabine
* Drug: Leucovorin
* Drug: Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female at least 18 years of age Must have gastric cancer or gastroesophageal junction cancer that cannot be operated on and that is advanced or has spread out Did not receive neoadjuvant or adjuvant treatment (chemotherapy, radiotherapy, or both) for their disease within the last 6 months Must have full activity or, if limited, must be able to walk and carry out light activities such as light house work or office work Must agree to provide tumor tissue sample, either from a previous surgery or biopsy within 6 months or fresh, prior to the start of treatment in this study Exclusion Criteria: Presence of tumor cells in the brain or spinal cord that have not been treated Active known or suspected autoimmune disease Any serious or uncontrolled medical disorder or active infection Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Any positive test result for hepatitis B or C indicating acute or chronic infection Other protocol-defined inclusion/exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab + Ipilimumab<br>Nivolumab + Ipilimumab for 4 doses, followed by Nivolumab monotherapy Enrollment is closed for this arm | Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Drug: Ipilimumab<br>* Specified dose on specified days<br>* Other names: BMS-734016;|
| Active Comparator: XELOX (Oxaliplatin + Capecitabine)<br> | Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Capecitabine<br>* Specified dose on specified days<br>|
| Active Comparator: FOLFOX (Oxaliplatin + Leucovorin + Fluorouracil)<br> | Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Leucovorin<br>* Specified dose on specified days<br>Drug: Fluorouracil<br>* Specified dose on specified days<br>|
| Experimental: Nivolumab + XELOX<br> | Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Capecitabine<br>* Specified dose on specified days<br>|
| Experimental: Nivolumab + FOLFOX<br> | Drug: Nivolumab<br>* Specified dose on specified days<br>* Other names: BMS-936558;Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Leucovorin<br>* Specified dose on specified days<br>Drug: Fluorouracil<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy With PD-L1 CPS ≥ 5 | Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS (combined positive score) ≥ 5. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From the date of randomization up to the date of death, up to approximately 17 months | 
| Progression Free Survival (PFS) in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy With PD-L1 CPS ≥ 5 | Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented PD or death due to any cause. PD is determined by blinded independent committee review (BICR) per RECIST1.1 criteria in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS ≥ 5. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 10 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy | Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy with PD-L1 CPS ≥ 1, 10, and all randomized participants. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From the date of randomization up to the date of death, up to approximately 17 months | 
| PFS in Participants Treated With Nivolumab Plus Chemotherapy vs Chemotherapy | Progression free survival (PFS), defined as the time from randomization to the date of the first documented progressive disease (PD) or death due to any cause, in participants treated with Nivolumab plus Chemotherapy vs Chemotherapy by BICR per RECIST1.1 in participants with PD-L1 CPS ≥ 10, 1, or all randomized subjects. Progreessive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 10 months) | 
| Objective Response Rate | Objective response rate (ORR) as assessed by BICR in participants with PD-L1 CPS ≥ 10, 5, 1, or all randomized participants. ORR is a percentage of participants determined by the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of measurable participants with target lesion at baseline. BOR is defined as the best response designation as determined by the BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1 as determined by the BICR) or the date of subsequent anti-cancer therapy, whichever occurs first. CR is defined as the disappearance of all target lesions. PR is define as at 30% decrease in the sum of diameters of target lesions. The 806 chemotherapy treated participants are split into two separate arms (Arm 2a and Arm 2b) to act as comparison groups to the other treatment arms. | From randomization to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 43 months) | 
| OS in Participants Treated With Nivolumab Plus Ipilimumab vs Chemotherapy | Overall survival (OS), defined as the time from randomization to the time of death, in participants treated with Nivolumab plus Ipilimumab vs Chemotherapy with PD-L1 CPS (combined positive score) ≥ 1, 5, 10, and all randomized participants. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From the date of randomization up to the date of death, up to approximately 14 months | 
| Time to Symptom Deterioration (TTSD) | TTSD is defined as the the time from randomization until a clinically meaningful decline from baseline in Gastric Cancer Subscale (GaCS) score. A clinically meaningful deterioration is defined as a reduction of 8.2 points in the GaCS score. Subjects who do not deteriorate will be censored at the time of their last GACS assessment. Subjects without baseline GaCS assessment will be censored on the randomization date. Those with baseline GaCS, who do not have any GaCS assessments after randomization will be censored on the day after randomization. | From randomization until a clinically meaningful decline from baseline in GaCS score | 
| PFS in Participants Treated With Nivolumab Plus Ipilimumab vs Chemotherapy | Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented PD or death due to any cause. PD is determined by blinded independent committee review (BICR) per RECIST1.1 criteria in participants treated with Nivolumab plus Ipilumab vs Chemotherapy with PD-L1 CPS ≥ 10, 5, 1 or all randomized participants. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking in reference the smallest sum on study that also demonstrated an absolute increase of at least 5 mm. CPS is defined as the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. | From randomization to the date of the first documented progressive disease (PD) per BICR or death due to any cause (up to approximately 9 months) |