Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate 067)

Study Overview
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Brief Summary
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The purpose of this study is to show that Nivolumab and/or Nivolumab in combination with Ipilimumab will extend progression free survival and overall survival compared to Ipilimumab alone.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab Versus Ipilimumab Monotherapy in Subjects With Previously Untreated Unresectable or Metastatic Melanoma

Conditions
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Unresectable or Metastatic Melanoma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Biological: Placebo for Nivolumab
* Biological: Placebo for Ipilimumab


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Histologically confirmed stage III (unresectable) or stage IV melanoma Treatment naïve patients Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria Tumor tissue from an unresectable or metastatic site of disease for biomarker analyses Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Exclusion Criteria: Active brain metastases or leptomeningeal metastases Ocular melanoma Subjects with active, known or suspected autoimmune disease Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Nivolumab+Placebo for Ipilimumab+Placebo for Nivolumab<br>Nivolumab 3 mg/kg solution intravenously every 2 weeks plus Placebo matching with Ipilimumab 0 mg/kg solution intravenously on weeks 1, 4 and Placebo matching with Nivolumab on weeks 4 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends | Biological: Nivolumab<br> <br> * Other names: MDX-1106;Biological: Placebo for Nivolumab<br> <br> Biological: Placebo for Ipilimumab<br> <br> |
| Experimental: Arm B: Nivolumab+Ipilimumab+Placebo for Nivolumab<br>Nivolumab 1 mg/kg solution intravenously combined with Ipilimumab 3 mg/kg solution intravenously every 3 weeks for 4 doses then Nivolumab 3 mg/kg solution intravenously every 2 weeks plus Placebo matching with Nivolumab on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends | Biological: Nivolumab<br> <br> * Other names: MDX-1106;Biological: Ipilimumab<br> <br> * Other names: MDX-010;Biological: Placebo for Nivolumab<br> <br> |
| Experimental: Arm C: Ipilimumab+Placebo for Nivolumab<br>Ipilimumab 3 mg/kg solution intravenously every 3 weeks for a total of 4 doses plus Placebo matching with Nivolumab 0 mg/kg solution intravenously on weeks 3 and 5 for cycles 1 and 2, until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends (Placebo matching with Nivolumab is no longer required) | Biological: Ipilimumab<br> <br> * Other names: MDX-010;Biological: Placebo for Nivolumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Progression is defined, using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, and an absolute increase of at least 5 mm. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants who started anti-cancer therapy without prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. | From randomization until disease progression or death, whichever occurred first (assessed up to February 2015, approximately 20 months) | 
| Overall Survival (OS) | OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. | From randomization to date of death (Assessed up to September 2016, approximately 39 months) | 
| Rate of Overall Survival | OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. The overall survival rate at time T (6, 12, or 24 months) was defined as the probability that a participant was alive at time T following randomization. | 6, 12, and 24 months | 
| Rate of Progression-Free Survival | PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Participants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. | 6, 12, and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS data is presented as it was in Primary Outcome Measure #1. The statistical analysis following this outcome measure (#5) reports on a secondary objective comparing PFS between the Nivolumab and Nivolumab + Ipilimumab arms. | From randomization until disease progression or death, whichever occurred first (assessed up to February 2015, approximately 20 months) | 
| Overall Survival (OS) | OS data is presented as it was in Primary Outcome Measure #2. The statistical analysis following this outcome measure (#6) reports on a secondary objective comparing OS between the Nivolumab and Nivolumab + Ipilimumab arms. | From randomization to date of death (Assessed up to September 2016, approximately 39 months) | 
| Objective Response Rate (ORR) Per Investigator Assessment | The ORR was defined as the number of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each arm. The BOR was defined as the best response designation, as determined by the Investigator, recorded between the date of randomization and the date of progression, as assessed by the Investigator per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurred first. For participants without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response designations contributed to the BOR assessment. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measureable disease and no new sites; Stable Disease (SD)= Failure to attain CR/PR or PD; Progressive Disease (PD)= Any new lesion or increase by >=50% of previously involved sites from nadir. | From randomization until date of disease progression or the date of subsequent anti-cancer therapy, whichever occurs first (Assessed up to February 2015, approximately 20 months) | 
| Progression-Free Survival Based on PD-L1 Expression Level | PD-L1 expression was defined as the percent of tumor cells demonstrating plasma membrane PD-L1 staining of any intensity using an IHC assay. Tumor biopsy specimens without measurable PD-L1 expression were classified as indeterminate if the staining was hampered for reasons attributed to the biology of the specimen and not because of improper specimen preparation or handling. Missing specimens, specimens that were not optimally collected (ie not evaluable), and all other specimens were classified as unknown. Participants must have been classified as PD-L1 >=5% or PD-L1 <5% per a verified IHC assay, or as indeterminate (ie not unknown), in order to be randomized. | From randomization until disease progression or death from any cause, whichever occurs first (Assessed up to September 2016, approximately 39 months) | 
| Overall Survival Based on PD-L1 Expression Level | OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. | From randomization until date of death (Assessed up to September 2016, approximately 39 months) | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. The mean score for all participants in an arm at a given week was subtracted from the mean score of the participants in that arm at baseline. Mean changes from baseline score is presented for all participants in an arm that remained on treatment and completed the EORTC-QLQ-C30 questionnaire at that time point. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation | 
| Mean Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning | Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline. | Baseline and weeks 5, 7, 11, 13, 17, 19, 23, 25, then every 6 weeks until treatment discontinuation |