A Study to Evaluate Efficacy in Subjects With Esophageal Cancer Treated With Nivolumab and Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin

Official Title
-----------------
A Randomized Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin in Subjects With Unresectable Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma

Conditions
-----------------
Various Advanced Cancer

Intervention / Treatment
-----------------
* Biological: Nivolumab
* Biological: Ipilimumab
* Drug: Cisplatin
* Drug: Fluorouracil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must have histologically confirmed squamous cell carcinoma or adenosquamous cell carcinoma of esophagus Male or Female at least 18 years of age Must have esophageal cancer that cannot be operated on, or treated with definitive chemoradiation with curative intent, that is advanced, reoccurring or has spread out 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 which are symptomatic or require treatment 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 and/or detectable virus Other protocol defined inclusion/exclusion criteria apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo (Nivolumab);Biological: Ipilimumab<br>* Specified dose on specified days<br>* Other names: Yervoy (Ipilimumab);|
| Experimental: Nivolumab + Cisplatin + Fluorouacil<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo (Nivolumab);Drug: Cisplatin<br>* Specified dose on specified days<br>Drug: Fluorouracil<br>* Specified dose on specified days<br>|
| Active Comparator: Cisplatin + Fluorouracil<br> | Drug: Cisplatin<br>* Specified dose on specified days<br>Drug: Fluorouracil<br>* Specified dose on specified days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in Participants With Tumor Cell PD-L1 | Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive. | From the date of randomization to up to the date of death (up to approximately 20 months) | 
| Progression-free Survival (PFS) as Assessed by BICR in Participants With Tumor Cell PD-L1 | Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. | From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) in All Randomized Participants | Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive. | From the date of randomization to up to the date of death (up to approximately 16 months) | 
| Progression-free Survival (PFS) in All Randomized Participants as Assessed by BICR | Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. | From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 7 months) | 
| Objective Response Rate (ORR) as Assessed by BICR | Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Complete response is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm. | From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 40 months) |