Study of Nivolumab (BMS-936558) Plus Ipilimumab Compared With Ipilimumab Alone in the Treatment of Previously Untreated, Unresectable, or Metastatic Melanoma

Study Overview
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Brief Summary
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The primary purpose of this study is to compare the objective response rate, as determined by investigators, of Nivolumab combined with Ipilimumab versus Ipilimumab monotherapy in patients with untreated, unresectable, or metastatic melanoma

Official Title
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Phase 2, Randomized, Double Blinded, Study of Nivolumab (BMS-936558) in Combination With Ipilimumab vs Ipilimumab Alone in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Conditions
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Unresectable Melanoma, Metastatic Melanoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ipilimumab
* Drug: Placebo


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 Key Inclusion Criteria: Eastern Cooperative Oncology Group performance status of 0 or 1 Histologically confirmed unresectable Stage III or Stage IV melanoma No prior systemic anticancer therapy for unresectable or metastatic melanoma. Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to date of first dose, and all related adverse events have either returned to baseline or stabilized Tumor tissue obtained in the metastatic setting or from an unresectable site must be provided for biomarker analyses and sent to the central laboratory. Biopsy should be excisional, incisional punch, or core needle. Fine needle aspirates or other cytology samples are insufficient Known BRAF V600 mutation status as determined by an FDA-approved test. Patients with either V600 wild-type or V600 mutation-positive melanoma are eligible. Key Exclusion Criteria: Active brain metastases or leptomeningeal metastases. Patients with treated brain metastases are eligible if there is no evidence of progression on magnetic resonance imaging scan for at least 8 weeks after completion of treatment and within 28 days prior to first dose of study drug administration. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (>10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Ocular melanoma Patients with active, known, or suspected autoimmune disease. Those with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

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: Nivolumab + Ipilimumab<br>Participants received (Part 1) 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then (Part 2) 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion. | Drug: Nivolumab<br> <br> * Other names: Opdivo, BMS-936558;Drug: Ipilimumab<br> <br> * Other names: Yervoy;|
| Experimental: Placebo + Ipilimumab<br>Participants received (Part 1) placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then (Part 2) placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion. | Drug: Ipilimumab<br> <br> * Other names: Yervoy;Drug: Placebo<br>* Matching nivolumab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) - BRAF Wild-type (WT) Participants | Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) - BRAF Wild-type (WT) Participants | PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates. | From randomization to progression or death (up to approximately 88 months) | 
| Objective Response Rate (ORR) - BRAF Mutant Participants | Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months) | 
| Progression-Free Survival (PFS) - BRAF Mutant Participants | PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs 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 died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates. | From randomization to progression or death (up to approximately 88 months) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QOL) C30 Score | The EORTC QLQ-C30 version 3 is a questionnaire developed to assess the QOL of cancer patients. The questionnaire is a 30-item tool, and it comprises 6 functional subscales (physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as 9 symptom subscales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores for each subscale range from 0 to 100. For the 6 functional subscales, a higher score represents a better level of functioning/health status. For the 9 symptom subscales, a lower score represents a better outcome (low level of symptomatology). Scores for the 15 subscales are presented individually. | From Baseline (prior to start of study treatment) to Week 25 after first dose |