A Study of Two Different Dose Combinations of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Study Overview
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Brief Summary
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The purpose of this study is to evaluate two different dose combinations of nivolumab and ipilimumab in the treatment of melanoma.

Official Title
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Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination With Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination With Ipilimumab 3 mg/kg in Subjects With Previously Untreated, Unresectable or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Nivolumab 3 mg/kg IV
* Biological: Ipilimumab 1 mg/kg IV
* Biological: Nivolumab 1 mg/kg IV
* Biological: Ipilimumab 3 mg/kg IV
* Biological: Nivolumab 6 mg/kg IV


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Subject must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma [per American Joint Committee on Cancer (AJCC) staging system] that is unresectable or metastatic Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Subject has not been treated by systemic anticancer therapy for unresectable or metastatic melanoma Exclusion Criteria: Subjects with active brain metastases or leptomeningeal metastases Subjects with ocular melanoma Subjects with active, known or suspected autoimmune disease Other protocol defined inclusion/exclusion criteria could 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV<br>Specified dose on specified days | Biological: Nivolumab 3 mg/kg IV<br>* Followed by Nivolumab monotherapy<br>Biological: Ipilimumab 1 mg/kg IV<br>* Followed by Nivolumab monotherapy<br>|
| Experimental: Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV<br>Specified dose on specified days | Biological: Nivolumab 1 mg/kg IV<br> <br> Biological: Ipilimumab 3 mg/kg IV<br> <br> |
| Experimental: Nivolumab 6 mg/kg IV + Ipilimumab 1 mg/kg<br>Specified dose on specified days | Biological: Ipilimumab 1 mg/kg IV<br>* Followed by Nivolumab monotherapy<br>Biological: Nivolumab 6 mg/kg IV<br>* A dose of 240mg is identical to a dose of 3mg/kg, therefore 6mg/kg is approximately equal to   480mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Participants With Drug-Related Grade 3 - 5 Adverse Events (AEs) | The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria. | From first dose of study treatment up to primary completion date 20-Apr-2017 (up to approximately 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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, as determined by the investigator, recorded between the date of randomization and the date of progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled at Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization to date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 5 years) | 
| Overall Survival (OS) | The time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Based on Kaplan-Meier Estimates. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up tp approximately 5 years) | 
| Progression Free Survival (PFS) | The time between the date of randomization and the first date of documented progression, determined by the investigator, or death due to any cause, whichever occurs first. Participants who die without a reported progression will be considered to have progressed on the date of their death. Those who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants without on study tumor assessments and who did not die will be censored on their date of randomization. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Based on Kaplan-Meier Estimates. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From randomization to the first date of documented progression or death due to any cause, whichever occurs first (up to approximately 5 years) | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Physical Functioning Scale sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Role Functioning Scale sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Emotional Functioning Scale sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Cognitive Functioning Scale sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Social Functioning Scale sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 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. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Dyspnea sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Insomnia sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Appetite loss sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Constipation sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Diarrhea sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points. | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Financial difficulties sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Fatigue sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Nausea and Vomiting sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points for the various scales of the EORTC QLQ-C30 | Weeks 7, 16, 20, 24, 28, 32, 36, 40 | 
| Mean Changes From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain | Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Pain sub-scale 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 indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points | Weeks 7, 16, 20, 24, 28, 32, 36, 40 |