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)
NCT ID: NCT01866319
Last Updated: 2020-06-02
Study Results
Results available
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View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
834 participants
Study Classification
INTERVENTIONAL
Study Start Date
2013-08-28
Study Completion Date
2019-06-03
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).
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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.
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.
Conditions
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Melanoma
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Ipilimumab
Participants receive ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).
Group Type
EXPERIMENTAL
Ipilimumab
Intervention Type
BIOLOGICAL
3 mg/kg IV Q3W.
Pembrolizumab Q2W
Participants receive pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.
Group Type
EXPERIMENTAL
Pembrolizumab
Intervention Type
BIOLOGICAL
10 mg/kg IV, administered Q2W or Q3W based upon randomization.
Pembrolizumab Q3W
Participants receive pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
Group Type
ACTIVE_COMPARATOR
Pembrolizumab
Intervention Type
BIOLOGICAL
10 mg/kg IV, administered Q2W or Q3W based upon randomization.
Interventions
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Pembrolizumab
10 mg/kg IV, administered Q2W or Q3W based upon randomization.
Intervention Type
BIOLOGICAL
Ipilimumab
3 mg/kg IV Q3W.
Intervention Type
BIOLOGICAL
Other Intervention Names
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MK-3475
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
* 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
* 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
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Merck Sharp & Dohme LLC
References
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Robert C,Schachter J,Long GV,Arance A,Grob JJ,Mortier L,Daud A,Carlino MS,McNeil C,Lotem M,Larkin J,Lorigan P,Neyns B,Blank CU,Hamid O,Mateus C,Shapira-Frommer R,Kosh M,Zhou H,Ibrahim N,Ebbinghaus S,Ribas A,KEYNOTE-006 investigators . Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Apr 19; PMID: 25891173
Reference Type
BACKGROUND
Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017 Oct 21;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X. Epub 2017 Aug 16.
Reference Type
RESULT
Long GV, Carlino MS, McNeil C, Ribas A, Gaudy-Marqueste C, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance AM, Daud AI, Hamid O, Larkin J, Yao L, Singh R, Lal R, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol. 2024 Dec;35(12):1191-1199. doi: 10.1016/j.annonc.2024.08.2330. Epub 2024 Sep 15.
Reference Type
DERIVED
Robert C, Carlino MS, McNeil C, Ribas A, Grob JJ, Schachter J, Nyakas M, Kee D, Petrella TM, Blaustein A, Lotem M, Arance A, Daud AI, Hamid O, Larkin J, Anderson J, Krepler C, Grebennik D, Long GV. Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma. J Clin Oncol. 2023 Aug 20;41(24):3998-4003. doi: 10.1200/JCO.22.01599. Epub 2023 Jun 22.
Reference Type
DERIVED
Hamid O, Robert C, Daud A, Carlino MS, Mitchell TC, Hersey P, Schachter J, Long GV, Hodi FS, Wolchok JD, Arance A, Grob JJ, Joshua AM, Weber JS, Mortier L, Jensen E, Diede SJ, Moreno BH, Ribas A. Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006. Eur J Cancer. 2021 Nov;157:391-402. doi: 10.1016/j.ejca.2021.08.013. Epub 2021 Sep 25.
Reference Type
DERIVED
Robert C, Hwu WJ, Hamid O, Ribas A, Weber JS, Daud AI, Hodi FS, Wolchok JD, Mitchell TC, Hersey P, Dronca R, Joseph RW, Boutros C, Min L, Long GV, Schachter J, Puzanov I, Dummer R, Lin J, Ibrahim N, Diede SJ, Carlino MS, Joshua AM. Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Eur J Cancer. 2021 Feb;144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.
Reference Type
DERIVED
Lala M, Li TR, de Alwis DP, Sinha V, Mayawala K, Yamamoto N, Siu LL, Chartash E, Aboshady H, Jain L. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020 May;131:68-75. doi: 10.1016/j.ejca.2020.02.016. Epub 2020 Apr 15.
Reference Type
DERIVED
van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T. Immunogenicity of pembrolizumab in patients with advanced tumors. J Immunother Cancer. 2019 Aug 8;7(1):212. doi: 10.1186/s40425-019-0663-4.
Reference Type
DERIVED
Robert C, Ribas A, Schachter J, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Su SC, Krepler C, Ibrahim N, Long GV. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019 Sep;20(9):1239-1251. doi: 10.1016/S1470-2045(19)30388-2. Epub 2019 Jul 22.
Reference Type
DERIVED
Wang M, Chen C, Jemielita T, Anderson J, Li XN, Hu C, Kang SP, Ibrahim N, Ebbinghaus S. Are tumor size changes predictive of survival for checkpoint blockade based immunotherapy in metastatic melanoma? J Immunother Cancer. 2019 Feb 8;7(1):39. doi: 10.1186/s40425-019-0513-4.
Reference Type
DERIVED
Hamid O, Robert C, Ribas A, Hodi FS, Walpole E, Daud A, Arance AS, Brown E, Hoeller C, Mortier L, Schachter J, Long J, Ebbinghaus S, Ibrahim N, Butler M. Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006. Br J Cancer. 2018 Sep;119(6):670-674. doi: 10.1038/s41416-018-0207-6. Epub 2018 Sep 11.
Reference Type
DERIVED
Carlino MS, Long GV, Schadendorf D, Robert C, Ribas A, Richtig E, Nyakas M, Caglevic C, Tarhini A, Blank C, Hoeller C, Bar-Sela G, Barrow C, Wolter P, Zhou H, Emancipator K, Jensen EH, Ebbinghaus S, Ibrahim N, Daud A. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial. Eur J Cancer. 2018 Sep;101:236-243. doi: 10.1016/j.ejca.2018.06.034. Epub 2018 Aug 7.
Reference Type
DERIVED
Petrella TM, Robert C, Richtig E, Miller WH Jr, Masucci GV, Walpole E, Lebbe C, Steven N, Middleton MR, Hille D, Zhou W, Ibrahim N, Cebon J. Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. Eur J Cancer. 2017 Nov;86:115-124. doi: 10.1016/j.ejca.2017.08.032. Epub 2017 Oct 4.
Reference Type
DERIVED
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.
Reference Type
DERIVED
Study Documents
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Document Type: CSR Synopsis
View DocumentRelated Links
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http://merckoncologyclinicaltrials.com
Merck Oncology Clinical Trials Information
Other Identifiers
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2012-004907-10
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
MK-3475-006
Identifier Type: OTHER
Identifier Source: secondary_id
3475-006
Identifier Type: -
Identifier Source: org_study_id
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