Study to Evaluate the Safety and Efficacy of Two Different Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Participants With Advanced Melanoma (MK-3475-006/KEYNOTE-006)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of 2 different dosing schedules of pembrolizumab (MK-3475), every 2 weeks (Q2W) and every 3 weeks (Q3W), and compare the 2 schedules to treatment with ipilimumab in ipilimumab-naïve participants with unresectable or metastatic melanoma. The primary hypotheses are that pembrolizumab is superior to ipilimumab with respect to progression-free survival (PFS) and overall survival (OS).

Detailed Description
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Participants assigned to a primary course of pembrolizumab can receive up to 24 months of treatment. Participants with Stable Disease (SD) or better will then proceed to Post Treatment Follow-up. All efficacy and safety analyses will be based on the primary pembrolizumab course. Participants who experience disease progression during the Post Treatment Follow-up will be eligible for a Second Course of pembrolizumab treatment for up to 1 additional year. With Amendment 05, all Second Course participants will be treated with a fixed dose of pembrolizumab 200 mg Q3W. With Amendment 06, after the study has achieved its key objectives or the study has ended, participants will be discontinued from this study and enrolled in an extension study to continue protocol-defined assessments and treatment.

Official Title
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A Multicenter, Randomized, Controlled, Three-Arm, Phase III Study to Evaluate the Safety and Efficacy of Two Dosing Schedules of Pembrolizumab (MK-3475) Compared to Ipilimumab in Patients With Advanced Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed diagnosis of unresectable Stage III or metastatic melanoma not amenable to local therapy (excluding uveal or ocular melanoma) At least one measurable lesion No prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (first line) or one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for melanoma (second line) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Archived tissue sample or new biopsy sample Female participants of childbearing potential must agree to use effective contraception from Visit 1 to 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug Exclusion criteria: Prior treatment with ipilimumab or other anti-cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agent or any anti-programmed cell death (PD-1 or PD-L2) agent Chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or not recovered from adverse events caused by cancer therapeutics administered more than four weeks earlier Currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug Expected to require any other form of systemic or localized antineoplastic therapy while on study On any systemic steroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication History of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration, excluding adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases are eligible Severe hypersensitivity reaction to treatment with another monoclonal antibody Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents Active infection requiring systemic therapy Known history of Human Immunodeficiency Virus (HIV) Known history of or positive for Hepatitis B or C Known psychiatric or substance abuse disorder Regular user (including recreational use) of illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol) Pregnant or breastfeeding, or expecting to conceive, or father children within the projected duration of the study Received a live vaccine within 30 days prior to first dose of study drug

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: Ipilimumab<br>Participants receive ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months). | Biological: Ipilimumab<br>* 3 mg/kg IV Q3W.<br>|
| Experimental: Pembrolizumab Q2W<br>Participants receive pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months. | Biological: Pembrolizumab<br>* 10 mg/kg IV, administered Q2W or Q3W based upon randomization.<br>* Other names: MK-3475;|
| Active Comparator: Pembrolizumab Q3W<br>Participants receive pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months. | Biological: Pembrolizumab<br>* 10 mg/kg IV, administered Q2W or Q3W based upon randomization.<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Independent Radiology Plus Oncology Review (IRO) | PFS was defined as the time from randomization to the first documented disease progression, based on blinded Independent Radiology plus Oncology review (IRO) using RECIST 1.1, or death due to any cause, whichever occurred first. Disease progression was defined as a 20% or greater increase in the sum of diameters of target lesions with an absolute increase of at least 5 mm or the appearance of new lesions. The primary analysis of PFS was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014. | Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014) | 
| Percentage of Participants With Overall Survival (OS) at 12 Months | OS was defined as the time from randomization to death due to any cause. The percentage of participants with OS (OS rate) at 12 months was reported for each arm. The reported percentage was estimated using a product-limit (Kaplan-Meier) method for censored data; data were censored at the date of cut-off. The primary analysis of OS was performed at the time of the second protocol pre-specified statistical analysis, with data cut-off of 03-Mar-2015. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO | ORR was defined as the percentage of the participants with a best tumor response of complete response (CR: disappearance of all target lesions with any pathological lymph nodes having a reduction in short axis to <10 mm) or partial response (PR: ≥30% decrease in the sum of diameters of target lesions), based on IRO using RECIST 1.1. The primary analysis of ORR was performed at the time of the first protocol pre-specified statistical analysis, with data cut-off of 03-Sep-2014. | Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)