A Study of Nivolumab, Nivolumab Plus Ipilimumab, or Investigator's Choice Chemotherapy for the Treatment of Participants With Deficient Mismatch Repair (dMMR)/Microsatellite Instability High (MSI-H) Metastatic Colorectal Cancer (mCRC)

Study Overview
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Brief Summary
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The main purpose of this study is to compare the clinical benefit, as measured by Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS), achieved by nivolumab in combination with ipilimumab or by nivolumab monotherapy in participants with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) metastatic colorectal cancer (mCRC). This study will also compare nivolumab plus ipilimumab combination vs chemotherapy for treatment of MSI-H/dMMR mCRC participants.

Official Title
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A Phase 3 Randomized Clinical Trial of Nivolumab Alone, Nivolumab in Combination With Ipilimumab, or Investigator's Choice Chemotherapy in Participants With Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: Ipilimumab
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Fluorouracil
* Drug: Irinotecan
* Drug: Bevacizumab
* Drug: Cetuximab
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed recurrent or metastatic colorectal cancer (CRC) irrespective of prior treatment history with chemotherapy and/or targeted agents not amenable to surgery (Applicable only during Part 1 enrollment of the study) Histologically confirmed recurrent or metastatic CRC with no prior treatment history with chemotherapy and/or targeted agents for metastatic disease and not amenable to surgery (Applicable during Part 2 enrollment of the study) Known tumor microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) status per local standard of practice Eastern cooperative oncology group (ECOG) performance status lower than or equal to 1 Exclusion Criteria: An active, known or suspected autoimmune disease History of interstitial lung disease or pneumonitis Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) 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: Arm A: Nivolumab Monotherapy<br> | Biological: Nivolumab<br>* Specified dose on specified days<br>|
| Experimental: Arm B: Nivolumab + Ipilimumab Combination<br> | Biological: Ipilimumab<br>* Specified dose on specified days<br>Biological: Nivolumab<br>* Specified dose on specified days<br>|
| Active Comparator: Arm C: Investigator's Choice Chemotherapy<br>Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress | 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>Drug: Irinotecan<br>* Specified dose on specified days<br>Drug: Bevacizumab<br>* Specified dose on specified days<br>Drug: Cetuximab<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 |
| --- | --- | --- |
| Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) (arm B vs A, all lines, centrally confirmed) |  | Up to 5 years | 
| PFS by BICR (arm B vs C, 1L, centrally confirmed) |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) by BICR (arm B vs A, all lines, centrally confirmed) |  | Up to 5 years | 
| Overall Survival (OS) (arm B vs A, all lines, centrally confirmed) |  | Up to 5 years | 
| PFS by Investigator Assessment (arm B vs A, all lines, centrally confirmed) |  | Up to 5 years | 
| PFS by BICR among all randomized participants (arm B vs A, all lines, per local testing) |  | Up to 5 years | 
| PFS by BICR (arm B vs A, 1L, centrally confirmed) |  | Up to 5 years | 
| ORR by BICR (arm B vs C, 1L, centrally confirmed) |  | Up to 5 years | 
| ORR by BICR (arm B vs A, 1L, centrally confirmed) |  | Up to 5 years | 
| OS (arm B vs A, 1L, centrally confirmed) |  | Up to 5 years | 
| PFS by BICR (arm A vs C, 1L, centrally confirmed) |  | Up to 5 years | 
| OS (arm B vs C, 1L, centrally confirmed) |  | Up to 5 years | 
| ORR by BICR (arm A vs C, 1L, centrally confirmed) |  | Up to 5 years | 
| OS (arm A vs C, 1L, centrally confirmed) |  | Up to 5 years | 
| PFS by Investigator (arm A, B and C, 1L, centrally confirmed) |  | Up to 5 years | 
| PFS by BICR among all randomized participants who have not received prior treatment (arm B vs C, 1L, per local testing) |  | Up to 5 years | 
| PFS by BICR among all randomized participants who have not received prior treatment (arm B vs A, 1L, per local testing) |  | Up to 5 years | 
| PFS by BICR (arm B vs C, 1L, by each central test) |  | Up to 5 years | 
| PFS by BICR (arm B vs A, all lines, by each central test) |  | Up to 5 years | 
| PFS by BICR (crossover cohort, centrally confirmed) |  | Up to 5 years | 
| ORR by BICR (crossover cohort, centrally confirmed) |  | Up to 5 years |