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
Trial Snapshot
- Phase
- Phase 3
- Status
- Active, not recruiting
- Sponsor
- Bristol-Myers Squibb
- Enrollment
- 839
- Locations
- 314
- Primary Endpoint
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm C 1L Participants Centrally Confirmed MSI-H/dMMR
Study Overview
Brief Summary
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Irinotecan (Drug)
Arm A: Nivolumab Monotherapy
Intervention: Nivolumab (Biological)
Arm B: Nivolumab + Ipilimumab Combination
Intervention: Nivolumab (Biological)
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Fluorouracil (Drug)
Arm B: Nivolumab + Ipilimumab Combination
Intervention: Ipilimumab (Biological)
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Leucovorin (Drug)
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Oxaliplatin (Drug)
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Bevacizumab (Drug)
Arm C: Investigator's Choice Chemotherapy
Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress
Intervention: Cetuximab (Drug)
Outcomes
Primary Outcomes
Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm C 1L Participants Centrally Confirmed MSI-H/dMMR
Time Frame: From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months)
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm A All Lines Centrally Confirmed MSI-H/dMMR
Time Frame: From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months)
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm A All Lines Centrally Confirmed MSI-H/dMMR
Time Frame: From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months)
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm C 1L Participants Centrally Confirmed MSI-H/dMMR
Time Frame: From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months)
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
Secondary Outcomes
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - 1L Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first)
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm A All Randomized Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - 1L Randomized Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Crossover and First Line Arm(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first)
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Polymerase Chain Reaction (PCR) - Arm B vs. Arm A(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Immunohistochemistry (IHC) - Arm B vs. Arm A(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Investigator - Arm A and Arm B All Lines With dMMR/MSI-H mCRC(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Polymerase Chain Reaction (PCR) - Arm B vs. Arm C(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Immunohistochemistry (IHC) - Arm B vs. Arm C(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months))
- Objective Response Rate (ORR) by Blinded Independent Review Center (BICR) - Arm A and Arm B All Lines With dMMR/MSI-H mCRC(From date of randomization to the date of the initial objectively documented tumor progression, or the date of initiation of subsequent therapy, whichever occurs first (Up to approximately 60 months))
- Objective Response Rate (ORR) by Blinded Independent Review Center (BICR) - 1L Participants(From date of randomization to the date of the initial objectively documented tumor progression, or the date of initiation of subsequent therapy, whichever occurs first (Up to approximately 60 months))
- Overall Survival (OS) - Arm B vs. Arm A All Lines With dMMR/MSI-H mCRC(From randomization to the date of death due to any cause (Up to approximately 60 months))
- Overall Survival (OS) - 1L Participants(From randomization to the date of death due to any cause)
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - 1L Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first)
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Arm B vs. Arm A All Randomized Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - 1L Randomized Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) - Crossover and First Line Arm(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first)
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Polymerase Chain Reaction (PCR) - Arm B vs. Arm A(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Immunohistochemistry (IHC) - Arm B vs. Arm A(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Polymerase Chain Reaction (PCR) - Arm B vs. Arm C(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months))
- Progression-free Survival (PFS) by Blinded Independent Review Center (BICR) by Immunohistochemistry (IHC) - Arm B vs. Arm C(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 32 months))
- Progression-free Survival (PFS) by Investigator- Arm B vs. Arm A All Lines(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Investigator - Arm A and Arm B All Lines With dMMR/MSI-H mCRC(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months))
- Progression-free Survival (PFS) by Investigator - 1L Participants(From date of randomization to the date of first objectively documented disease progression or death due to any cause, whichever occurs first (Up to approximately 60 months for arm A and arm B; up to 32 months for arm C))
- Objective Response Rate (ORR) by Blinded Independent Review Center (BICR) - Arm A and Arm B All Lines With dMMR/MSI-H mCRC(From date of randomization to the date of the initial objectively documented tumor progression, or the date of initiation of subsequent therapy, whichever occurs first (Up to approximately 60 months))
- Objective Response Rate (ORR) by Blinded Independent Review Center (BICR) - 1L Participants(From date of randomization to the date of the initial objectively documented tumor progression, or the date of initiation of subsequent therapy, whichever occurs first (Up to approximately 60 months))
- Overall Survival (OS) - Arm B vs. Arm A All Lines With dMMR/MSI-H mCRC(From randomization to the date of death due to any cause (Up to approximately 60 months))
- Overall Survival (OS) - 1L Participants(From randomization to the date of death due to any cause)