Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)

Melanoma Clinical Trial

Official title:

Adjuvant Therapy With Pembrolizumab Versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE-716)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03553836
• Other study ID #: 3475-716
• Secondary ID: MK-3475-716KEYNO
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 12, 2018
• Est. completion date: October 12, 2033

Study information

• Verified date: February 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This 2-part study will evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma. Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design every 3 weeks (Q3W) for up to 17 cycles/~1 year (each cycle = 21 days). Participants who complete the initial treatment of 17 cycles of pembrolizumab in Part 1 and experience disease recurrence may be eligible for re-challenge with pembrolizumab at the same dose and schedule of 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design. Participants who complete the initial treatment of placebo and experience disease recurrence may be eligible to switch over to pembrolizumab 200 mg Q3W (21-day cycles) for up to 35 cycles (up to ~2 years) in Part 2 in an open label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo.

Per protocol, response/ progression or adverse events (AEs) during re-challenge/switch-over in Part 2 will not be counted towards the RFS outcome measure or safety outcome measures respectively.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 976
• Est. completion date: October 12, 2033
• Est. primary completion date: June 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion:

• Has surgically resected and histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer (AJCC) 8th edition guidelines

• Has not been previously treated for melanoma beyond complete surgical resection

• Has =12 weeks between final surgical resection and randomization

• Has no evidence of metastatic disease on imaging as determined by investigator

• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale or Lansky Play-Performance Scale (LPS) score =50 for participants =16 years old, or a Karnofsky Performance Scale (KPS) score =50 for participants >16 and <18 years old

• Has recovered adequately from toxicity and/or complications from surgery prior to study start

• Female participants must not be pregnant or breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment if they are women of childbearing potential (WOCBP)

Exclusion:

• Has a known additional malignancy that is progressing or has required active antineoplastic therapy (including hormonal) within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment

• WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-Programmed Cell Death Receptor Ligand 1 (PD-L1) or anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)

• Has received prior systemic anti-cancer therapy for melanoma including investigational agents

• Has received a live vaccine within 30 days prior to the first dose of study treatment

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment

• Has severe hypersensitivity (=Grade 3) to any excipients of pembrolizumab

• Has an active autoimmune disease that has required systemic treatment in the past 2 years

• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

• Has an active infection requiring systemic therapy

• Has a known history of human immunodeficiency virus (HIV) infection

• Has a known history of hepatitis B (defined as hepatitis B surface antigen reactive) or known active hepatitis C virus (defined as hepatitis C virus ribonucleic acid [RNA] [qualitative] is detected) infection

• Has a history of active tuberculosis (Bacillus tuberculosis)

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator

• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

• Has had an allogeneic tissue/solid organ transplant

Related Conditions & MeSH terms

• Melanoma

Intervention

Biological:
• Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)

Other:
• Placebo
Administered as an IV infusion every 3 weeks (Q3W)

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital ( Site 0861)	Adelaide	South Australia
Australia	Cairns Base Hospital ( Site 0859)	Cairns	Queensland
Australia	Ashford Cancer Centre Research ( Site 0860)	Kurralta Park	South Australia
Australia	The Alfred Hospital ( Site 0852)	Melbourne	Victoria
Australia	Fiona Stanley Hospital ( Site 0851)	Murdoch	Western Australia
Australia	Melanoma Institute Australia ( Site 0856)	North Sydney	New South Wales
Australia	Tasman Oncology Research Pty Ltd ( Site 0858)	Southport	Queensland
Australia	Westmead Hospital ( Site 0853)	Westmead	New South Wales
Australia	Princess Alexandra Hospital ( Site 0857)	Woolloongabba	Queensland
Belgium	Cliniques Universitaires Saint-Luc ( Site 0251)	Brussels	Bruxelles-Capitale, Region De
Belgium	Institut Jules Bordet ( Site 0254)	Bruxelles	Bruxelles-Capitale, Region De
Belgium	UZ Gent ( Site 0255)	Gent	Oost-Vlaanderen
Belgium	Jessa Ziekenhuis Campus Virga Jesse ( Site 0256)	Hasselt	Limburg
Belgium	UZ Leuven ( Site 0252)	Leuven	Vlaams-Brabant
Belgium	GZA Sint Augustinus ( Site 0259)	Wilrijk - Antwerpen	Antwerpen
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0155)	Barretos	Sao Paulo
Brazil	Hospital Erasto Gaertner ( Site 0159)	Curitiba	Parana
Brazil	Hospital de Caridade de Ijui ( Site 0156)	Ijui	Rio Grande Do Sul
Brazil	Hospital Sao Vicente de Paulo ( Site 0158)	Passo Fundo	Rio Grande Do Sul
Brazil	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 0154)	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto Nacional do Cancer II ( Site 0160)	Rio de Janeiro
Brazil	Hospital de Clinicas de Rio Preto ( Site 0162)	Sao Jose Do Rio Preto - SP	Sao Paulo
Brazil	A.C. Camargo Cancer Center ( Site 0164)	Sao Paulo
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 0151)	Sao Paulo
Brazil	Real e Benemerita Associacao Portuguesa de Beneficencia ( Site 0161)	Sao Paulo
Canada	Cross Cancer Institute ( Site 0057)	Edmonton	Alberta
Canada	Moncton Hospital - Horizon Health Network ( Site 0055)	Moncton	New Brunswick
Canada	Hopital Maisonneuve Rosemont ( Site 0056)	Montreal	Quebec
Canada	Jewish General Hospital ( Site 0054)	Montreal	Quebec
Canada	McGill University Health Centre ( Site 0062)	Montreal	Quebec
Canada	The Ottawa Hospital ( Site 0058)	Ottawa	Ontario
Canada	CHU de Quebec - Hotel-Dieu de Quebec ( Site 0061)	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0059)	Toronto	Ontario
Canada	Sunnybrook Research Institute ( Site 0060)	Toronto	Ontario
Canada	CancerCare Manitoba ( Site 0053)	Winnipeg	Manitoba
Chile	Centro Oncologico Antofagasta ( Site 0206)	Antofagasta
Chile	Fundacion Arturo Lopez Perez FALP ( Site 0200)	Santiago	Region M. De Santiago
Chile	Pontificia Universidad Catolica de Chile ( Site 0201)	Santiago	Region M. De Santiago
Chile	Sociedad Medica Aren y Bachero Limitada ( Site 0207)	Santiago	Region M. De Santiago
Chile	Instituto Clinico Oncologico del Sur ( Site 0203)	Temuco	Araucania
Chile	Oncocentro ( Site 0204)	Vina del Mar	Valparaiso
France	CHU Amiens Picardie Hopital Nord ( Site 0317)	Amiens	Somme
France	CHU Angers ( Site 0321)	Angers	Maine-et-Loire
France	CHU de Bordeaux- Hopital Saint Andre ( Site 0304)	Bordeaux	Gironde
France	Hopital Ambroise Pare Boulogne ( Site 0316)	Boulogne-Billancourt	Hauts-de-Seine
France	CHU Dijon Bourgogne ( Site 0320)	Dijon	Cote-d Or
France	CHRU Lille - Hopital Claude Huriez ( Site 0301)	Lille	Nord
France	Hopital La Timone ( Site 0302)	Marseille	Bouches-du-Rhone
France	CHU Montpellier. ( Site 0312)	Montpellier	Herault
France	Hopital Saint Louis ( Site 0322)	Paris
France	C.H.U. Lyon Sud ( Site 0303)	Pierre Benite	Rhone
France	CHU de Reims ( Site 0307)	Reims	Marne
France	Centre Eugene Marquis ( Site 0305)	Rennes	Ille-et-Vilaine
France	Institut Claudius Regaud IUCT Oncopole ( Site 0306)	Toulouse	Haute-Garonne
France	Institut Gustave Roussy ( Site 0300)	Villejuif	Val-de-Marne
Germany	Elbe Klinikum Buxtehude ( Site 0354)	Buxtehude	Niedersachsen
Germany	Klinik und Poliklinik fuer Dermatologie Venerologie und Allergologie ( Site 0361)	Essen	Nordrhein-Westfalen
Germany	SRH Wald-Klinikum Gera GmbH ( Site 0360)	Gera	Thuringen
Germany	Universitaetsklinikum Hamburg Eppendorf (UKE) ( Site 0352)	Hamburg
Germany	Medizinische Hochschule Hannover ( Site 0358)	Hannover	Niedersachsen
Germany	Universitaetsklinikum Schleswig-Holstein Campus Kiel ( Site 0359)	Kiel	Schleswig-Holstein
Germany	Universitaetsklinikum in Mannheim ( Site 0351)	Mannheim	Baden-Wurttemberg
Germany	Klinikum der Ludwig-Maximilians-Universitaet Muenchen ( Site 0357)	Muenchen	Bayern
Germany	Klinikum Nuernberg Nord ( Site 0355)	Nuernberg	Bayern
Germany	Universitaetsklinikum Tuebingen ( Site 0353)	Tuebingen	Baden-Wurttemberg
Germany	Klinikum der Universitaet in Wuerzburg ( Site 0356)	Wuerzburg	Bayern
Israel	HaEmek Medical Center ( Site 0655)	Afula
Israel	Soroka Medical Center ( Site 0653)	Beer Sheva	Southern
Israel	Rambam Medical Center ( Site 0654)	Haifa
Israel	Hadassah Ein Kerem Medical Center ( Site 0651)	Jerusalem
Israel	Chaim Sheba Medical Center. ( Site 0652)	Ramat Gan
Israel	Sourasky Medical Center ( Site 0656)	Tel Aviv	Tell Abib
Israel	Shamir Medical Center-Assaf Harofeh ( Site 0657)	Zerifin
Italy	IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0406)	Bari
Italy	ASST Papa Giovanni XXIII ( Site 0402)	Bergamo
Italy	IRCCS A.O.U. San Martino - IST ( Site 0404)	Genova
Italy	Istituto Scientifico Romagnolo per Studio e Cura Tumori IRST ( Site 0403)	Meldola	Forli-Cesena
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0408)	Milano
Italy	Istituto Nazionale Tumori Fondazione Pascale ( Site 0400)	Napoli
Italy	IRCCS Istituto Oncologico Veneto ( Site 0407)	Padova
Italy	IDI - Istituto Dermopatico dell'Immacolata ( Site 0405)	Roma
Italy	Azienda Ospedaliero Universitaria Senese ( Site 0401)	Siena
Japan	National Cancer Center Hospital ( Site 0910)	Tokyo
Poland	Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 0754)	Bielsko-Biala	Slaskie
Poland	Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 0769)	Bydgoszcz	Kujawsko-pomorskie
Poland	Uniwersyteckie Centrum Kliniczne ( Site 0770)	Gdansk	Pomorskie
Poland	Uniwersyteckie Centrum Kliniczne Slaskiego Uniwersytetu Medycznego ( Site 0757)	Katowice	Slaskie
Poland	Pratia MCM Krakow ( Site 0773)	Krakow	Malopolskie
Poland	Szpital Kliniczny im. Heliodora Swiecickiego Uniwers Medyczn ( Site 0753)	Poznan	Wielkopolskie
Poland	LIFTMED ( Site 0765)	Rybnik	Slaskie
Poland	Kliniczny Szpital Wojewodzki Nr 1 ( Site 0758)	Rzeszow	Podkarpackie
Poland	Instytut Pomnik Centrum Zdrowia Dziecka ( Site 0759)	Warszawa	Mazowieckie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie ( Site 0751)	Warszawa	Mazowieckie
South Africa	Cancercare ( Site 0810)	Cape Town	Limpopo
South Africa	Sandton Oncology Medical Group PTY LTD ( Site 0801)	Johannesburg	Gauteng
South Africa	Cape Town Oncology Trials Pty Ltd ( Site 0807)	Kraaifontein	Western Cape
South Africa	Charlotte Maxeke Johannesburg Academic Hospital ( Site 0811)	Parktown	Gauteng
South Africa	Cancer Care Langenhoven Drive Oncology Centre ( Site 0812)	Port Elizabeth	Eastern Cape
South Africa	MPOC ( Site 0803)	Pretoria	Gauteng
South Africa	Wilgers Oncology Centre ( Site 0806)	Pretoria	Gauteng
Spain	Hospital Clinic de Barcelona ( Site 0452)	Barcelona
Spain	Hospital General Universitari Vall d Hebron ( Site 0456)	Barcelona
Spain	Hospital General Universitario Gregorio Maranon ( Site 0454)	Madrid
Spain	Onkologikoa - Instituto Oncologico de San Sebastian ( Site 0457)	San Sebastian	Gipuzkoa
Spain	Hospital Universitario Virgen Macarena ( Site 0455)	Sevilla
Spain	Hospital General Universitario de Valencia ( Site 0451)	Valencia	Valenciana, Comunitat
Switzerland	Universitaetsspital Basel ( Site 0554)	Basel	Basel-Stadt
Switzerland	Oncological Institute of Southern Switzerland ( Site 0557)	Bellinzona	Ticino
Switzerland	Universitaetsspital Bern ( Site 0552)	Bern	Berne
Switzerland	Kantonsspital Graubuenden ( Site 0555)	Chur	Grisons
Switzerland	Hopitaux Universitaires de Geneve HUG ( Site 0556)	Geneva	Geneve
Switzerland	Centre Hospitalier Universitaire Vaudois ( Site 0553)	Lausanne	Vaud
Switzerland	Hopital du Valais ( Site 0558)	Sion	Wallis
Switzerland	Kantonsspital St. Gallen ( Site 0559)	St. Gallen	Sankt Gallen
Switzerland	Universitaetsspital Zuerich ( Site 0551)	Zuerich	Zurich
United Kingdom	Addenbrooke's Hospital in Cambridge ( Site 0600)	Cambridge	Cambridgeshire
United Kingdom	Guy s & St Thomas NHS Foundation Trust ( Site 0601)	London	London, City Of
United Kingdom	Royal Marsden Hospital - Fulham Road London ( Site 0613)	London	London, City Of
United Kingdom	Christie NHS Foundation Trust ( Site 0604)	Manchester
United Kingdom	The Royal Marsden NHS Foundation Trust. ( Site 0612)	Sutton	Surrey
United States	Northside Hospital ( Site 0115)	Atlanta	Georgia
United States	Winship Cancer Institute of Emory University ( Site 0046)	Atlanta	Georgia
United States	University of Colorado Cancer Center ( Site 0027)	Aurora	Colorado
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 0047)	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center ( Site 0141)	Boston	Massachusetts
United States	Dana Farber Cancer Institute ( Site 0124)	Boston	Massachusetts
United States	Massachusetts General Hospital ( Site 0126)	Boston	Massachusetts
United States	Northwestern Medical Group ( Site 0135)	Chicago	Illinois
United States	The University of Chicago Medical Center ( Site 0007)	Chicago	Illinois
United States	The Lindner Center for Research and Education at The Christ Hospital ( Site 0004)	Cincinnati	Ohio
United States	Karmanos Cancer Institute ( Site 0111)	Detroit	Michigan
United States	Inova Schar Cancer Institute ( Site 0014)	Fairfax	Virginia
United States	West Cancer Center - East Campus ( Site 0022)	Germantown	Tennessee
United States	Memorial Sloan Kettering ( Site 0006)	Harrison	New York
United States	University of Texas-MD Anderson Cancer Center ( Site 0134)	Houston	Texas
United States	University of Iowa Hospital and Clinics ( Site 0001)	Iowa City	Iowa
United States	Mayo Clinic Florida ( Site 0024)	Jacksonville	Florida
United States	University of Tennessee Medical Center Knoxville ( Site 0116)	Knoxville	Tennessee
United States	UCSD Moores Cancer Center ( Site 0133)	La Jolla	California
United States	The Angeles Clinic and Research Institute ( Site 0029)	Los Angeles	California
United States	UCLA Hematology & Oncology ( Site 0130)	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics ( Site 0030)	Madison	Wisconsin
United States	Yale University ( Site 0035)	New Haven	Connecticut
United States	Laura and Isaac Perlmutter Cancer Center ( Site 0137)	New York	New York
United States	Memorial Sloan Kettering Cancer Center ( Site 0142)	New York	New York
United States	Mount Sinai Medical Center ( Site 0038)	New York	New York
United States	Stephenson Cancer Center ( Site 0042)	Oklahoma City	Oklahoma
United States	Advocate Medical Group-Park Ridge ( Site 0025)	Park Ridge	Illinois
United States	Children's Hospital of Pittsburgh UPMC ( Site 0144)	Pittsburgh	Pennsylvania
United States	UPMC Hillman Cancer Centers ( Site 0043)	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University ( Site 0032)	Portland	Oregon
United States	VCU Massey Cancer Center ( Site 0008)	Richmond	Virginia
United States	Mayo Clinic [Rochester, MN] ( Site 0016)	Rochester	Minnesota
United States	University of Rochester ( Site 0019)	Rochester	New York
United States	Siteman Cancer Center ( Site 0143)	Saint Louis	Missouri
United States	John Wayne Cancer Institute ( Site 0026)	Santa Monica	California
United States	Seattle Cancer Care Alliance ( Site 0044)	Seattle	Washington
United States	Moffitt McKinley Outpatient Center ( Site 0131)	Tampa	Florida
United States	University of Arizona Cancer Center ( Site 0121)	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Chile,  France,  Germany,  Israel,  Italy,  Japan,  Poland,  South Africa,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrence-free Survival (RFS)	RFS was defined as the time from randomization to any of the following events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or distant recurrence) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or death due to any cause, whichever occurs first. Per protocol, final analysis for this primary outcome measure was performed using the initial pembrolizumab or placebo treatment with a protocol-specified analysis data cut-off date of June-21-2021.	Up to ~32.7 months
Secondary	Distant Metastasis-free Survival (DMFS)	DMFS will be defined as the time from randomization to the first diagnosis of a distant metastasis per RECIST 1.1. Distant metastasis will refer to cancer that has spread from the original (primary) tumor and beyond local tissues and lymph nodes to distant organs or distant lymph nodes. DMFS will be reported for randomized participants.	Up to ~9 years
Secondary	Overall Survival (OS)	OS will be defined as the time from randomization to death due to any cause. OS will be reported for randomized participants.	Up to ~15 years
Secondary	Number of Participants Who Experienced at Least One Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.	Up to ~19.3 months
Secondary	Number of Participants Who Discontinued Study Treatment Due to an AE	An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Per protocol, analysis for this outcome measure was performed using the initial pembrolizumab or placebo treatment.	Up to ~19.3 months

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary