An Investigational Immunotherapy Study of Nivolumab With Standard of Care Therapy vs Standard of Care Therapy for First-Line Treatment of Colorectal Cancer That Has Spread

Study Overview
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Brief Summary
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This purpose of this study is to evaluate nivolumab (BMS-936558) in combination with standard of care (SOC) chemotherapy with bevacizumab for the treatment of first-line metastatic colorectal cancer (mCRC).

Official Title
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An Open-Label Exploratory Phase 2/3 Study of Nivolumab With Standard of Care Therapy vs Standard of Care Therapy for First-Line Treatment of Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic colorectal cancer, not amenable to curative resection No prior chemotherapy for metastatic colorectal cancer ECOG Performance Status of 0-1 Ability to provide adequate tissue sample Exclusion Criteria: Patients with clinically relevant medical history, including autoimmune disease, cardiovascular disease, hepatic disease or bleeding disorders Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus 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<br>Nivo + SOC | Biological: Nivolumab<br>* Specified dose on specified days<br>* Other names: Opdivo;Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Leucovorin<br>* Specified dose on specified days<br>* Other names: Calcium Folinate;Drug: Fluorouracil<br>* Specified dose on specified days<br>Drug: Bevacizumab<br>* Specified dose on specified days<br>* Other names: Avastin;|
| Active Comparator: Arm B<br>SOC | Drug: Oxaliplatin<br>* Specified dose on specified days<br>Drug: Leucovorin<br>* Specified dose on specified days<br>* Other names: Calcium Folinate;Drug: Fluorouracil<br>* Specified dose on specified days<br>Drug: Bevacizumab<br>* Specified dose on specified days<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Per Blinded Independent Central Review (BICR) | Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented progression, as determined by BICR (per RECIST 1.1), or death due to any cause, whichever occurs first. Baseline tumor assessment is defined as tumor scans prior to or on randomization date. Participants who did not have documented progression per BICR and who did not die or participants who started any subsequent anti-cancer therapy without a prior reported progression per BICR will be censored at the date of the last tumor assessment on or prior to initiation of the subsequent anticancer therapy, if any. Participants who die without a reported prior progression per BICR will be considered to have progressed on the date of death. Participants who did not have any baseline or post baseline tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. | From randomization to up to the date of the first documented progression (up to 16 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Per Investigator Assessment | Progression Free Survival (PFS) is defined as the time from randomization to the date of the first documented progression, as determined by Investigator Assessment, or death due to any cause, whichever occurs first. Baseline tumor assessment is defined as tumor scans prior to or on randomization date. Participants who did not have documented progression per Investigator Assessment and who did not die or participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the date of the last tumor assessment on or prior to initiation of the subsequent anticancer therapy, if any. Participants who die without a reported prior progression per Investigator Assessment will be considered to have progressed on the date of death. Participants who did not have any baseline or post baseline tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. | From randomization up to the date of the first documented progression (up to approximately 44 months) | 
| Objective Response Rate (ORR) Per Blinded Independent Central Review (BICR) | ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response designation as determined by BICR per RECIST 1.1, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR 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 up to the date of objectively documented progression or the date of subsequent anticancer therapy, whichever occurs first (up to approximately 44 months) | 
| Objective Response Rate (ORR) Per Investigator Assessment | ORR is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response designation as determined by tumor assessments by the Investigator per RECIST 1.1, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR 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 up to the date of objectively documented progression or the date of subsequent anticancer therapy, whichever occurs first (up to approximately 44 months) | 
| Duration of Response (DoR) Per Blinded Independent Central Review (BICR) | Duration of objective response (DoR) is defined as the time between the date of first confirmed complete response (CR) or partial response (PR) to the date of the first documented tumor progression as assessed by the BICR based on RECIST 1.1 criteria or death due to any cause, whichever occurs first. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm. | From randomization up to the date of the first documented progression (per RECIST 1.1) or death due to any cause, whichever occurs first (up to 44 months) | 
| Duration of Response (DoR) Per Investigator Assessment | Duration of objective response (DoR) is defined as the time between the date of first confirmed complete response (CR) or partial response (PR) to the date of the first documented tumor progression as assessed by the investigator based on RECIST 1.1 criteria or death due to any cause, whichever occurs first. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm. | From randomization up to the date of the first documented progression (per RECIST 1.1) or death due to any cause, whichever occurs first (up to 44 months) | 
| Time to Objective Response Per Blinded Independent Central Review (BICR) | Time to objective response (TTR) is defined as the time from the randomization date to the date of the first confirmed complete response (CR) or partial response (PR) as assessed by BICR. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm. TTR is derived for responders only. | From the randomization date up to the date of the first confirmed CR or PR (up to approximately 44 months) | 
| Time to Objective Response Per Investigator Assessment | TTR is defined as the time from the randomization date to the date of the first confirmed complete response (CR) or partial response (PR) as assessed by investigator. PR is defined as at least a 30% decrease in the sum of diameters of target lesions. CR is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm. TTR is derived for responders only. | From the randomization date up to the date of the first confirmed CR or PR (up to 44 months) | 
| Overall Survival (OS) | Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. | From the date of randomization up to the date of death (up to 44 months) | 
| Number of Participants With Adverse Events (AEs) | An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal. | From first dose to 30 days post last dose (up to 45 months) | 
| Number of Participants With Serious Adverse Events (SAEs) | Number of participants with any grade of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE v4.0) to determine safety and tolerability. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening (defined as an event in which the participant was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization. | From first dose to 30 days post last dose (up to 45 months) | 
| Number of Participants Experiencing Death | The number of participants who died during the treatment period | From first dose up to 6 weeks post last dose (up to 46 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Liver Tests | The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal | From first dose up to 30 days post last dose (up to 45 months) | 
| Number of Participants With Laboratory Abnormalities in Specific Thyroid Tests | The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal | From first dose up to 30 days post last dose (up to 45 months) | 
| Disease Control Rate (DCR) Per Blinded Independent Central Review (BICR) | Disease Control Rate (DCR) is defined as the percentage of participants whose Best Overall Response (BOR) is complete response (CR) or partial response (PR) or stable disease (SD). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. | From the date of randomization up to the date of objectively documented progression or the date of subsequent anticancer therapy, whichever occurs first (up to approximately 44 months) | 
| Disease Control Rate (DCR) Per Investigator | Disease Control Rate (DCR) is defined as the percentage of participants whose Best Overall Response (BOR) is complete response (CR) or partial response (PR) or stable disease (SD). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. | From the date of randomization up to the date of objectively documented progression or the date of subsequent anticancer therapy, whichever occurs first (up to approximately 44 months) |