A Safety and Efficacy Study of Multiple Administration Regimens for Nivolumab Plus Ipilimumab in Subjects With Melanoma

Study Overview
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Brief Summary
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This is a safety and efficacy study of different administration regimens of nivolumab plus Ipilimumab in subjects with previously untreated, unresectable or metastatic melanoma.

Official Title
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Phase IIIb, Randomized, Study of Multiple Administration Regimens for Nivolumab Plus Ipilimumab in Subjects With Previously Untreated Unresectable or Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab


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: Males and Females, ages 15 years ≥ of age (Except where local regulations and/or institutional policies do not allow for subjects < 18 years of age to participate) Subjects must have been diagnosed with stage III or/and stage IV histologically confirmed melanoma that is unresectable or metastatic Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Subjects have 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab and Ipilimumab Concomitant Administration<br>Followed by Nivolumab monotherapy | Biological: Nivolumab<br>* -Specified dose on specified days<br>Biological: Ipilimumab<br>* -Specified dose on specified days<br>|
| Experimental: Nivolumab and Ipilimumab Sequential Administration<br>Followed by Nivolumab monotherapy | Biological: Nivolumab<br>* -Specified dose on specified days<br>Biological: Ipilimumab<br>* -Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Affected by Adverse Events (AEs) in the Broad Scope MedDRA Anaphylactic Reaction Standardized MedDRA Queries (SMQ) | This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction broad scope SMQ. Such AEs include any acute systemic reaction characterized by a large list of terms, including (but not limited to) pruritus, urticaria, flushing, hypotension, respiratory distress, and vascular insufficiency. It also includes other signs and symptoms such as asthma, choking sensation, coughing, sneezing, and difficulty breathing due to laryngeal spasm and/or bronchospasm. Less frequent clinical presentations are also captured and include hyperventilation, sensation of foreign body, and ocular edema. | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Affected by AEs in the Narrow Scope MedDRA Anaphylactic Reaction SMQ | This outcome describes the percentage of participants experiencing at least 1 AE in the MedDRA Anaphylactic Reaction narrow scope SMQ. The narrow scope SMQ is composed of a large list of terms, including (but not limited to) anaphylactic shock and reaction, shock and shock symptoms, and circulatory collapse, among the others. | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | 
| Percentage of Participants Affected by Hypersensitivity/Infusion Reaction Select AEs | This outcome describes the percentage of participants experiencing at least 1 AE in the Hypersensitivity/Infusion select AEs category. The select AEs consist of a list of preferred terms defined by the Sponsor and represent AEs with a potential immune-mediated etiology. The following 5 MedDRA preferred terms are included in the hypersensitivity/infusion reaction select AE category: Anaphylactic Reaction, Anaphylactic Shock, Bronchospasm, Hypersensitivity, and Infusion Related Reaction | Within 2 days from administration of any of the 4 doses in part 1 period (approximately 12 weeks) | 
| Percentage of Participants Affected by All Causality Grade 3 - 5 AEs | This outcome describes the percentage of participants who experienced at least 1 AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria | From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months) | 
| Percentage of Participants Affected by Drug-related Grade 3 - 5 AEs | This outcome describes the percentage of participants who experienced at least 1 Drug-related AE of Grade 3 or higher defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria | From initial dose of study treatment and within 30 days of the last dose of study treatment (approximately 25 months) | 
| Geometric Mean Concentration of Ipilimumab at End of Infusion (EOI) |  | From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported. | 
| Geometric Mean Concentration of Nivolumab at End of Infusion (EOI) |  | From Cycle 1, Day 1 to Cycle 4, Day 1 (approximately 9 weeks). Each cycle lasts 3 weeks. Cycle 1 day 1, Cycle 2 day 1 and Cycle 4 day 1 values reported | 
| Geometric Mean Trough Concentration of Ipilimumab |  | From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks. | 
| Geometric Mean Trough Concentration of Nivolumab |  | From Cycle 2, Day 1 to Cycle 4, Day 1 (approximately 6 weeks). Each cycle lasts 3 weeks. | 
| Objective Response Rate (ORR) | The ORR is defined as the proportion of participants with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR). The BOR is defined as the best response designation, as determined by the investigator, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. | Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression (approximately 20 months) | 
| Progression Free Survival (PFS) | PFS is 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 occurs first. | From the date of randomization to the first date of documented progression (approximately 26 months) |