Study of Pembrolizumab (MK-3475) or Placebo With Chemoradiation in Participants With Locally Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-412/KEYNOTE-412)
NCT ID: NCT03040999
Last Updated: 2025-08-27
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
804 participants
INTERVENTIONAL
2017-04-05
2024-08-21
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Pembrolizumab + Cisplatin + CRT
Participants receive a priming dose of pembrolizumab before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of pembrolizumab and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of pembrolizumab alone as maintenance therapy for a total of 17 cycles of pembrolizumab. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with pembrolizumab.
Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
Cisplatin
100 mg/m\^2 administered as an IV infusion Q3W
Accelerated Fractionation (AFX) Radiotherapy
70 Gray (Gy) given in 35 fractions over 6 weeks
Standard Fractionation (SFX) Radiotherapy
70 Gy given in 35 fractions over 7 weeks
Placebo + Cisplatin + CRT
Participants receive placebo before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of placebo and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of placebo alone for a total of 17 cycles of placebo. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with placebo.
Placebo
Normal saline or dextrose solution administered as an IV infusion Q3W
Cisplatin
100 mg/m\^2 administered as an IV infusion Q3W
Accelerated Fractionation (AFX) Radiotherapy
70 Gray (Gy) given in 35 fractions over 6 weeks
Standard Fractionation (SFX) Radiotherapy
70 Gy given in 35 fractions over 7 weeks
Interventions
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Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
Placebo
Normal saline or dextrose solution administered as an IV infusion Q3W
Cisplatin
100 mg/m\^2 administered as an IV infusion Q3W
Accelerated Fractionation (AFX) Radiotherapy
70 Gray (Gy) given in 35 fractions over 6 weeks
Standard Fractionation (SFX) Radiotherapy
70 Gy given in 35 fractions over 7 weeks
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Has provided tissue for Programmed Cell Death Receptor Ligand 1 (PD-L1) biomarker analysis from a core or excisional biopsy. If an excisional or incisional biopsy has been performed, participants remain eligible for the study provided the residual disease meets the staging criteria required for the trial (e.g., excisional biopsy of a lymph node with residual T4 primary). Prior surgical debulking, including tonsillectomy, for the head and neck cancer under study is not allowed.
* Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on RECIST version 1.1
* Is eligible for definitive CRT and not considered for primary surgery based on investigator decision
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to receiving the first dose of study therapy
* Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy
* Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy
Exclusion Criteria
* Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-PD-L1, anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in clinical studies with pembrolizumab
* Has received a live vaccine within 30 days prior to the first dose of study therapy
* Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer
* Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical surgery for head and neck cancer under study
* Has not recovered from major surgery prior to starting study therapy
* Has known active Hepatitis B or C
* Has known history of Human Immunodeficiency Virus (HIV)
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
* Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has had previous allogeneic tissue/solid organ transplant
* Has active infection requiring systemic therapy
* Has a history of severe hypersensitivity reaction to pembrolizumab, Cisplatin or radiotherapy or their analogs
* Is pregnant or breast feeding or expecting to conceive or father children throughout the study period and for up to 180 days after the last dose of study therapy
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Merck Sharp & Dohme LLC
Locations
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UCLA Medical Center ( Site 0273)
Los Angeles, California, United States
University of California San Francisco ( Site 0274)
San Francisco, California, United States
St. Joseph Heritage Healthcare ( Site 0254)
Santa Rosa, California, United States
Smilow Cancer Hospital at Yale New Haven ( Site 0256)
New Haven, Connecticut, United States
Rush University Medical Center ( Site 0260)
Chicago, Illinois, United States
Indiana University ( Site 0264)
Indianapolis, Indiana, United States
Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital ( Site 0281)
Baton Rouge, Louisiana, United States
University of Massachusetts Memorial Medical Center ( Site 0285)
Worcester, Massachusetts, United States
University of Michigan Hospital and Health Systems ( Site 0267)
Ann Arbor, Michigan, United States
Barbara Ann Karmanos Cancer Institute ( Site 0272)
Detroit, Michigan, United States
Mercy Clinic Cancer and Hematology - Chub O'Reilly Cancer Center ( Site 0290)
Springfield, Missouri, United States
St. Vincent Healthcare Frontier Cancer Center ( Site 0286)
Billings, Montana, United States
Comprehensive Cancer Centers of Nevada ( Site 8004)
Las Vegas, Nevada, United States
University of Rochester - James P. Wilmot Cancer Center ( Site 0255)
Rochester, New York, United States
Oncology Hematology Care, Inc. ( Site 8003)
Cincinnati, Ohio, United States
Willamette Valley Cancer Institute and Research Center ( Site 8000)
Eugene, Oregon, United States
St. Luke's Cancer Center - Anderson ( Site 0251)
Easton, Pennsylvania, United States
St. Francis Hospital Cancer Center ( Site 1461)
Greenville, South Carolina, United States
Texas Oncology-Arlington North ( Site 8005)
Arlington, Texas, United States
Texas Oncology-Austin Central ( Site 8002)
Austin, Texas, United States
Texas Oncology PA ( Site 8001)
Longview, Texas, United States
University of Virginia Health System ( Site 0261)
Charlottesville, Virginia, United States
Seattle Cancer Care Alliance/Univ of Washington Medical Center ( Site 0269)
Seattle, Washington, United States
Medical Oncology Associates (Summit Cancer Centers) ( Site 0257)
Spokane, Washington, United States
Blacktown Hospital Western Sydney Local Health District ( Site 0304)
Blacktown, New South Wales, Australia
Liverpool Hospital ( Site 0301)
Liverpool, New South Wales (Australia), Australia
Princess Alexandra Hospital ( Site 0305)
Brisbane, Queensland, Australia
Royal Brisbane and Women s Hospital ( Site 0302)
Herston, Queensland, Australia
Royal Adelaide Hospital ( Site 0303)
Adelaide, South Australia, Australia
Peter MacCallum Cancer Centre ( Site 0300)
Melbourne, Victoria, Australia
Landeskrankenhaus - Universitatsklinikum Graz ( Site 0601)
Graz, , Austria
Krankenhaus der Barmherzigen Schwestern Linz ( Site 0603)
Linz, , Austria
Landeskrankenhaus Salzburg ( Site 0600)
Salzburg, , Austria
Allgemeines Krankenhaus der Stadt Wien ( Site 0602)
Vienna/Wien, , Austria
Cliniques Universitaires Saint Luc - Bruxelles ( Site 0651)
Brussels, , Belgium
UZ Gent ( Site 0650)
Ghent, , Belgium
UZ Leuven Campus Gasthuisberg ( Site 0652)
Leuven, , Belgium
C.H.U. Sart Tilman-Service d'Oncologie Medicale ( Site 0654)
Liège, , Belgium
Clinique et Maternite Sainte-Elisabeth ( Site 0653)
Namur, , Belgium
Centro Regional Integrado de Oncologia ( Site 0002)
Fortaleza, Ceará, Brazil
Hospital Santa Izabel - Santa Casa de Misericordia da Bahia ( Site 0006)
Salvador, Estado de Bahia, Brazil
Liga Norte Riograndense Contra o Cancer ( Site 0005)
Natal, Rio Grande do Norte, Brazil
Hospital de Clinicas de Porto Alegre ( Site 0011)
Porto Alegre, Rio Grande do Sul, Brazil
Hospital Nossa Senhora da Conceicao ( Site 0001)
Porto Alegre, Rio Grande do Sul, Brazil
Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0003)
Barretos, São Paulo, Brazil
Instituto do Cancer de Sao Paulo - ICESP ( Site 0004)
São Paulo, São Paulo, Brazil
Hospital das Clinicas da FMUSP de Ribeirao Preto ( Site 0008)
Ribeirão Preto, , Brazil
Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0010)
Rio de Janeiro, , Brazil
Tom Baker Cancer Centre ( Site 0063)
Calgary, Alberta, Canada
Cross Cancer Institute ( Site 0064)
Edmonton, Alberta, Canada
Juravinski Cancer Centre ( Site 0062)
Hamilton, Ontario, Canada
London Health Sciences Centre ( Site 0055)
London, Ontario, Canada
The Ottawa Hospital - Cancer Care ( Site 0052)
Ottawa, Ontario, Canada
Princess Margaret Cancer Centre ( Site 0051)
Toronto, Ontario, Canada
McGill University Health Centre ( Site 0061)
Montreal, Quebec, Canada
CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0057)
Sherbrooke, Quebec, Canada
Hospital Pablo Tobon Uribe ( Site 0151)
Medellín, Antioquia, Colombia
Fundacion Valle del Lili ( Site 0150)
Cali, Valle del Cauca Department, Colombia
Centro Medico Imbanaco de Cali S.A ( Site 0156)
Cali, Valle del Cauca Department, Colombia
Centro de Investigacion Clinica del Country ( Site 0155)
Bogotá, , Colombia
FN Brno. ( Site 0703)
Brno, , Czechia
Fakultni Nemocnice Hradec Kralove ( Site 0705)
Hradec Králové, , Czechia
Fakultni nemocnice Olomouc ( Site 0701)
Olomouc, , Czechia
Fakultni nemocnice Ostrava ( Site 0702)
Ostrava, , Czechia
2. LF UK a FN Motol ( Site 0704)
Prague, , Czechia
Nemocnice Na Bulovce ( Site 0700)
Prague, , Czechia
Centre Jean Bernard Laboratoire Mahe Meziani ( Site 0760)
Le Mans, , France
Clinique Francois Chenieux ( Site 0757)
Limoges, , France
Institut Claudius Regaud ( Site 0754)
Toulouse, , France
Institut De Cancerologie De Lorraine ( Site 0758)
Vandœuvre-lès-Nancy, , France
Institut Gustave Roussy ( Site 0759)
Villejuif, , France
Universitätsklinikum Erlangen ( Site 0801)
Erlangen, , Germany
SRH Waldklinikum Gera GmbH ( Site 0802)
Gera, , Germany
Universitares Cancer Center Hamburg - UCCH ( Site 0811)
Hamburg, , Germany
Medizinische Hochschule Hannover ( Site 0807)
Hanover, , Germany
Universitaetsklinikum Schleswig-Holstein-Campus Luebeck ( Site 0803)
Lübeck, , Germany
Klinikum der Universitaet Munchen ( Site 0810)
München, , Germany
Universitaetsklinik Ulm ( Site 0804)
Ulm, , Germany
Rambam MC ( Site 0903)
Haifa, , Israel
Hadassah Ein Karem Jerusalem ( Site 0902)
Jerusalem, , Israel
Rabin Medical Center ( Site 0904)
Petah Tikva, , Israel
Sheba MC ( Site 0901)
Ramat Gan, , Israel
Tel Aviv Sourasky Medical Center ( Site 0900)
Tel Aviv, , Israel
Azienda Ospedaliero Universitaria di Modena Policlinico ( Site 0954)
Modena, MO, Italy
Azienda Ospedaliero Universitaria Careggi ( Site 0955)
Florence, , Italy
Istituto Nazionale Tumori ( Site 0950)
Milan, , Italy
Istituto Europeo di Oncologia ( Site 0953)
Milan, , Italy
Azienda Ospedaliera San Paolo ( Site 0952)
Milan, , Italy
Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0951)
Napoli, , Italy
Istituto Oncologico Veneto ( Site 0957)
Padua, , Italy
Fondazione IRCCS - Policlinico San Matteo ( Site 0960)
Pavia, , Italy
National Cancer Center Hospital East ( Site 0350)
Kashiwa, Chiba, Japan
Hokkaido University Hospital ( Site 0351)
Sapporo, Hokkaido, Japan
Hyogo Cancer Center ( Site 0354)
Akashi, Hyōgo, Japan
Kagawa University Hospital ( Site 0359)
Kita-gun, Kagawa-ken, Japan
Miyagi Cancer Center ( Site 0353)
Natori-shi, Miyagi, Japan
Chiba Cancer Center ( Site 0358)
Chiba, , Japan
Hiroshima University Hospital ( Site 0352)
Hiroshima, , Japan
Osaka International Cancer Institute ( Site 0355)
Osaka, , Japan
Medical Hospital, Tokyo Medical And Dental University ( Site 0356)
Tokyo, , Japan
The Cancer Institute Hospital of JFCR ( Site 0357)
Tokyo, , Japan
Noordwest Ziekenhuisgroep NWZ ( Site 1350)
Alkmaar, , Netherlands
VU Medisch Centrum ( Site 1352)
Amsterdam, , Netherlands
UMCG ( Site 1351)
Groningen, , Netherlands
UMC St. Radboud ( Site 1356)
Nijmegen, , Netherlands
Erasmus University Medical Center ( Site 1354)
Rotterdam, , Netherlands
Capital & Coast District Health Board - Wellington Hospital ( Site 0400)
Wellington, Newtown, New Zealand
Dolnoslaskie Centrum Onkologii. ( Site 1001)
Wroclaw, Lower Silesian Voivodeship, Poland
Mazowiecki Szpital Onkologiczny ( Site 1015)
Wieliszew, Masovian Voivodeship, Poland
Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 1005)
Bielsko-Biala, , Poland
Szpital Morski im. PCK. Szpitale Pomorskie Sp. Z o.o ( Site 1007)
Gdynia, , Poland
Centrum Onkologii. Instytut im. Marii Sklodowskiej-Curie ( Site 1010)
Gliwice, , Poland
Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 1008)
Krakow, , Poland
Zachodniopomorskie Centrum Onkologii ( Site 1013)
Szczecin, , Poland
Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 1000)
Warsaw, , Poland
Seoul National University Bundang Hospital ( Site 0453)
Seongnam-si, Gyeonggi-do, South Korea
Chungbuk National University Hospital ( Site 0454)
Cheongju-si, North Chungcheong, South Korea
Chungnam National University Hospital ( Site 0455)
Daejeon, , South Korea
Severance Hospital Yonsei University Health System ( Site 0452)
Seoul, , South Korea
Samsung Medical Center ( Site 0450)
Seoul, , South Korea
H.U. Vall de Hebron ( Site 1052)
Barcelona, , Spain
Hospital Duran i Reynals ( Site 1053)
L'Hospitalet de Llobregat, , Spain
Hospital Doce de Octubre ( Site 1054)
Madrid, , Spain
Hospital Universitario Ramon y Cajal ( Site 1055)
Madrid, , Spain
Hospital Clinico San Carlos ( Site 1051)
Madrid, , Spain
Hospital Universitario Virgen de la Victoria ( Site 1056)
Málaga, , Spain
Hospital Gral Universitario de Valencia ( Site 1050)
Valencia, , Spain
Chang Gung Medical Foundation - Kaohsiung ( Site 0501)
Kaohsiung City, , Taiwan
Taichung Veterans General Hospital ( Site 0506)
Taichung, , Taiwan
National Cheng Kung University Hospital ( Site 0503)
Tainan City, , Taiwan
National Taiwan University Hospital ( Site 0500)
Taipei, , Taiwan
MacKay Memorial Hospital ( Site 0505)
Taipei, , Taiwan
Taipei Veterans General Hospital ( Site 0504)
Taipei, , Taiwan
Linkou Chang Gung Memorial Hospital ( Site 0502)
Taoyuan District, , Taiwan
Basken Adana Dr.Turgut Noyan Uygulama ve Arastirma Merkezi ( Site 1103)
Adana, , Turkey (Türkiye)
Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1102)
Ankara, , Turkey (Türkiye)
Ankara Sehir Hastanesi ( Site 1108)
Ankara, , Turkey (Türkiye)
Istanbul Universitesi Istanbul Tip Fakultesi ( Site 1100)
Istanbul, , Turkey (Türkiye)
Medipol Universite Hastanesi ( Site 1104)
Istanbul, , Turkey (Türkiye)
Medical Park Izmir Hastanesi ( Site 1109)
Izmir, , Turkey (Türkiye)
Kocaeli Universitesi Tip Fakultesi ( Site 1106)
Kocaeli, , Turkey (Türkiye)
Inonu Universitesi Tip Fakultesi ( Site 1101)
Malatya, , Turkey (Türkiye)
Norfolk & Norwich University Hospital NHS Foundation Trust ( Site 1206)
Norwich, Norfolk, United Kingdom
University Hospital of North Staffordshire ( Site 1202)
Stoke-on-Trent, Staffordshire, United Kingdom
Ipswich Hospital ( Site 1207)
Ipswich, Suffolk, United Kingdom
St Bartholomew s Hospital ( Site 1205)
London, , United Kingdom
The Royal Marsden Foundation Trust ( Site 1200)
London, , United Kingdom
Imperial Healthcare NHS Trust Charing Cross Hospital ( Site 1204)
London, , United Kingdom
Lancashire Teaching Hospitals NHS Foundation Trust ( Site 1208)
Preston, , United Kingdom
University Hospital Southampton NHS Foundation Trust ( Site 1203)
Southampton, , United Kingdom
Royal Marsden NHS Foundation Trust ( Site 1201)
Sutton, , United Kingdom
Countries
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References
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Machiels JP, Tao Y, Licitra L, Burtness B, Tahara M, Rischin D, Alves G, Lima IPF, Hughes BGM, Pointreau Y, Aksoy S, Laban S, Greil R, Burian M, Hetnal M, Delord JP, Mesia R, Taberna M, Waldron JN, Simon C, Gregoire V, Harrington KJ, Swaby RF, Zhang Y, Gumuscu B, Bidadi B, Siu LL; KEYNOTE-412 Investigators. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024 May;25(5):572-587. doi: 10.1016/S1470-2045(24)00100-1. Epub 2024 Mar 29.
Machiels JP, Tao Y, Burtness B, Tahara M, Licitra L, Rischin D, Waldron J, Simon C, Gregoire V, Harrington K, Alves GV, Figueiredo Lima IP, Pointreau Y, M Hughes BG, Aksoy S, Hetnal M, Ge JY, Brown H, Cheng J, Bidadi B, Siu LL. Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Future Oncol. 2020 Jun;16(18):1235-1243. doi: 10.2217/fon-2020-0184. Epub 2020 Jun 3.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Merck Clinical Trial Information
Other Identifiers
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MK-3475-412
Identifier Type: OTHER
Identifier Source: secondary_id
173640
Identifier Type: REGISTRY
Identifier Source: secondary_id
KEYNOTE-412
Identifier Type: OTHER
Identifier Source: secondary_id
2016-003934-25
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
3475-412
Identifier Type: -
Identifier Source: org_study_id
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