Study of Nivolumab (BMS-936558) Compared With Dacarbazine in Untreated, Unresectable, or Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to compare the clinical benefit, as measured by overall survival, of nivolumab with that of. dacarbazine in patients with previously untreated, unresectable, or metastatic melanoma

Official Title
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A Phase 3, Randomized, Double-Blind Study of BMS-936558 vs Dacarbazine in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: BMS-936558 (Nivolumab)
* Biological: Placebo matching BMS-936558 (Nivolumab)
* Drug: Dacarbazine
* Drug: Placebo matching Dacarbazine


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: Men and women ≥18 years of age Eastern Cooperative Oncology Group Performance Status of 0 or 1 Untreated and histologically confirmed unresectable Stage III or Stage IV melanoma, as per the staging system of the American Joint Committee on Cancer Measurable disease as per Response Evaluation Criteria in Solid Tumors 1.1 Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses Known BRAF wild-type, as per regionally acceptable V600 mutational status testing. BRAF mutant patients and those with indeterminate or unknown BRAF status are not permitted to randomize Exclusion Criteria: Active brain metastases or leptomeningeal metastases Ocular melanoma Any active, known, or suspected autoimmune disease

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab, 3 mg/kg<br>Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion. Eligible participants may switch to nivolumab at 480mg every 4 weeks until documented disease progression, discontinuation, withdrawal of consent or the study ends. | Biological: BMS-936558 (Nivolumab)<br> <br> Drug: Placebo matching Dacarbazine<br> <br> |
| Active Comparator: Dacarbazine, 1000 mg/m^2<br>Participants received dacarbazine, 1000 mg/m^2, solution administered IV every 3 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion. Eligible participants may cross-over to nivolumab open label treatment, either 3 mg/kg every 2 weeks or 480mg every 4 weeks until documented disease progression, discontinuation, withdrawal of consent or the study ends. | Biological: Placebo matching BMS-936558 (Nivolumab)<br> <br> Drug: Dacarbazine<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. | From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 17 months. | 
| Overall Survival (OS) Rate | OS rate is calculated as the percentage of participants alive at the indicated timepoints | From randomization to 6 months and or to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Investigator-assessed PFS is defined as the time from randomization to the date of the first documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Patients who died without progressing were considered to have progressed on the date of their death. Those who did not progress or die were documented on the date of their last evaluable tumor assessment. Patients who did not have any on-study tumor assessments and did not die were documented on their date of randomization. Those who started any subsequent anticancer therapy without a prior reported progression were documented on the date of their last evaluable tumor assessment prior to initiation of subsequent anticancer therapy. | From date of randomization up to date of disease progression or death, up to approximately 84 months | 
| Progression-free Survival (PFS) Rate | The PFS rate at a time point is the estimated percentage of patients who have not progressed and are alive at that time point following randomization and is estimated using the Kaplan-Meier methodology. | From randomization to the specified timepoints, up to 84 months | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants with a best overall response of Response Evaluation Criteria in Solid Tumors (RECIST) defined complete response (CR) or partial response (PR). RECIST, volume 1.1 for target lesions: CR=disappearance of all target lesions; PR=at least a 30% decrease in the sum of the longest dimension (LD) of target lesions, taking as reference the baseline sum LD; stable disease=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, and the sum LD must have an absolute increase of ≥5 mm. | Tumor assessments beginning at 9 weeks following randomization and continuing every 6 weeks for the first year, then every 12 weeks thereafter until disease progression or death, assessed to 94 months | 
| Overall Survival by Programmed Cell Death Ligand 1 (PD-L1) Expression Level | Overall Survival is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. PD-L1 expression level is defined as the percent of tumor cells demonstrating plasma membrane PD-L1-staining in a minimum of 100 evaluable tumor cells per a Dako PD-L1 IHC (immunohistochemistry) assay (referred to as quantifiable PD-L1 expression). Assessment of OS by PD-L1 expression as measured by a validated assay and comparing OS in patients with tumor PD-L1 expression ≥5% (PD-L1 positive) versus patients with tumor PD-L1 expression <5% (PD-L1 negative). Tumor tissue samples for PD-L1 testing were collected at screening from metastatic or unresectable sites prior to randomization. | From date of randomization to date of disease progression or death, up to approximately 94 months | 
| Change From Baseline in Health-related Quality of Life (HRQoL) Scores | HRQoL is evaluated by mean changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life composite scale in all randomized patients. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicate better quality of life (QoL), while higher scores on the symptom scales indicate declining QoL. | At baseline and every 6 weeks for 12 months and at follow-up visits 1 and 2, assessed up to 93 months |