NCT01866319 · CITED IN SOURCE DOCUMENTS

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)

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2020-06-02

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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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

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)

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outcome · POSTED

Percentage of Participants With Overall Survival (OS) at 12 Months

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outcome · POSTED

Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Participants receive ipilimumab, 3 mg/kg intravenously (IV), once every 3 weeks (Q3W) for a total of 4 doses (up to approximately 3 months).
intervention Names
Biological: Ipilimumab
label
Ipilimumab
type
EXPERIMENTAL
description
Participants receive pembrolizumab, 10 mg/kg IV, once every 2 weeks (Q2W) for up to approximately 24 months.
intervention Names
Biological: Pembrolizumab
label
Pembrolizumab Q2W
type
EXPERIMENTAL
description
Participants receive pembrolizumab, 10 mg/kg IV, Q3W for up to approximately 24 months.
intervention Names
Biological: Pembrolizumab
label
Pembrolizumab Q3W
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Pembrolizumab Q2W
Pembrolizumab Q3W
description
10 mg/kg IV, administered Q2W or Q3W based upon randomization.
name
Pembrolizumab
other Names
MK-3475
type
BIOLOGICAL
arm Group Labels
Ipilimumab
description
3 mg/kg IV Q3W.
name
Ipilimumab
type
BIOLOGICAL

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 834
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
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)
time Frame
Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)
description
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.
measure
Percentage of Participants With Overall Survival (OS) at 12 Months
time Frame
Month 12

secondary Outcomes

description
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.
measure
Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by IRO
time Frame
Up to approximately 12 months (through first pre-specified statistical analysis cut-off date of 03-Sep-2014)

Full study description

brief Summary: 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: 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.

Source references

avail Ipds

type
CSR Synopsis
url
http://www.merck.com/clinical-trials/study.html?id=3475-006&kw=3475-006&tab=access

references

citation
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
type
BACKGROUND
citation
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.
pmid
28822576
type
RESULT
citation
Shin E, Bhat AG, Ramanathan M. Large Language Models for Clinical Trial Protocol Assessments. Clin Pharmacol Ther. 2026 Feb;119(2):393-402. doi: 10.1002/cpt.70096. Epub 2025 Oct 21.
pmid
41121745
type
DERIVED
citation
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.
pmid
39306585
type
DERIVED
citation
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.
pmid
37348035
type
DERIVED
citation
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.
pmid
34571336
type
DERIVED
citation
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.
pmid
33360855
type
DERIVED
citation
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.
pmid
32305010
type
DERIVED
citation
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.
pmid
31395089
type
DERIVED
citation
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.
pmid
31345627
type
DERIVED
citation
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.
pmid
30736858
type
DERIVED
citation
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.
pmid
30202085
type
DERIVED