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)

A Randomized Phase III Study of Pembrolizumab Given Concomitantly With Chemoradiation and as Maintenance Therapy Versus Chemoradiation Alone in Subjects With Locally Advanced Head and Neck Squamous Cell Carcinoma (KEYNOTE-412)

The purpose of this study is to determine the efficacy and safety of pembrolizumab given concomitantly with chemoradiation (CRT) and as maintenance therapy versus placebo plus CRT in participants with locally advanced head and neck squamous cell carcinoma (LA HNSCC). The primary hypothesis is that pembrolizumab in combination with CRT is superior to placebo in combination with CRT with respect to event-free survival (EFS).

Study Overview

• Status: Completed
• Conditions: Head and Neck Neoplasms
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Cisplatin; Radiation: Accelerated Fractionation (AFX) Radiotherapy; Radiation: Standard Fractionation (SFX) Radiotherapy; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 804
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital Western Sydney Local Health District ( Site 0304)
  • New South Wales (Australia)
    • Liverpool, New South Wales (Australia), Australia, 2170
      • Liverpool Hospital ( Site 0301)
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital ( Site 0305)
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women s Hospital ( Site 0302)
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital ( Site 0303)
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre ( Site 0300)
• Austria
  • Graz, Austria, 8036
    • Landeskrankenhaus - Universitatsklinikum Graz ( Site 0601)
  • Linz, Austria, 4010
    • Krankenhaus der Barmherzigen Schwestern Linz ( Site 0603)
  • Salzburg, Austria, 5020
    • Landeskrankenhaus Salzburg ( Site 0600)
  • Vienna/Wien, Austria, 1090
    • Allgemeines Krankenhaus der Stadt Wien ( Site 0602)
• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc - Bruxelles ( Site 0651)
  • Ghent, Belgium, 9000
    • UZ Gent ( Site 0650)
  • Leuven, Belgium, 3000
    • UZ Leuven Campus Gasthuisberg ( Site 0652)
  • Liège, Belgium, 4000
    • C.H.U. Sart Tilman-Service d'Oncologie Medicale ( Site 0654)
  • Namur, Belgium, 5000
    • Clinique et Maternite Sainte-Elisabeth ( Site 0653)
• Brazil
  • Ribeirão Preto, Brazil, 14048-900
    • Hospital das Clinicas da FMUSP de Ribeirao Preto ( Site 0008)
  • Rio de Janeiro, Brazil, 20230-130
    • Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0010)
  • Ceará
    • Fortaleza, Ceará, Brazil, 60336-045
      • Centro Regional Integrado de Oncologia ( Site 0002)
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 40050-410
      • Hospital Santa Izabel - Santa Casa de Misericordia da Bahia ( Site 0006)
  • Rio Grande do Norte
    • Natal, Rio Grande do Norte, Brazil, 59075-740
      • Liga Norte Riograndense Contra o Cancer ( Site 0005)
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre ( Site 0011)
    • Porto Alegre, Rio Grande do Sul, Brazil, 91350-200
      • Hospital Nossa Senhora da Conceicao ( Site 0001)
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0003)
    • São Paulo, São Paulo, Brazil, 01246-000
      • Instituto do Cancer de Sao Paulo - ICESP ( Site 0004)
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre ( Site 0063)
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute ( Site 0064)
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre ( Site 0062)
    • London, Ontario, Canada, N6A 4L6
      • London Health Sciences Centre ( Site 0055)
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - Cancer Care ( Site 0052)
    • Toronto, Ontario, Canada, M5G 1X5
      • Princess Margaret Cancer Centre ( Site 0051)
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre ( Site 0061)
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0057)
• Colombia
  • Bogotá, Colombia, 110221
    • Centro de Investigacion Clinica del Country ( Site 0155)
  • Antioquia
    • Medellín, Antioquia, Colombia, 050034
      • Hospital Pablo Tobon Uribe ( Site 0151)
  • Valle del Cauca Department
    • Cali, Valle del Cauca Department, Colombia, 760032
      • Fundacion Valle del Lili ( Site 0150)
    • Cali, Valle del Cauca Department, Colombia, 760042
      • Centro Medico Imbanaco de Cali S.A ( Site 0156)
• Czechia
  • Brno, Czechia, 625 00
    • FN Brno. ( Site 0703)
  • Hradec Králové, Czechia, 500 05
    • Fakultni Nemocnice Hradec Kralove ( Site 0705)
  • Olomouc, Czechia, 775 20
    • Fakultni nemocnice Olomouc ( Site 0701)
  • Ostrava, Czechia, 708 52
    • Fakultni nemocnice Ostrava ( Site 0702)
  • Prague, Czechia, 150 06
    • 2. LF UK a FN Motol ( Site 0704)
  • Prague, Czechia, 180 81
    • Nemocnice Na Bulovce ( Site 0700)
• France
  • Le Mans, France, 72000
    • Centre Jean Bernard Laboratoire Mahe Meziani ( Site 0760)
  • Limoges, France, 87039
    • Clinique Francois Chenieux ( Site 0757)
  • Toulouse, France, 31059
    • Institut Claudius Regaud ( Site 0754)
  • Vandœuvre-lès-Nancy, France, 54500
    • Institut De Cancerologie De Lorraine ( Site 0758)
  • Villejuif, France, 94805
    • Institut Gustave Roussy ( Site 0759)
• Germany
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen ( Site 0801)
  • Gera, Germany, 07548
    • SRH Waldklinikum Gera GmbH ( Site 0802)
  • Hamburg, Germany, 20246
    • Universitares Cancer Center Hamburg - UCCH ( Site 0811)
  • Hanover, Germany, 30325
    • Medizinische Hochschule Hannover ( Site 0807)
  • Lübeck, Germany, 23538
    • Universitaetsklinikum Schleswig-Holstein-Campus Luebeck ( Site 0803)
  • München, Germany, 81377
    • Klinikum der Universitaet Munchen ( Site 0810)
  • Ulm, Germany, 89075
    • Universitaetsklinik Ulm ( Site 0804)
• Israel
  • Haifa, Israel, 3109601
    • Rambam MC ( Site 0903)
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Jerusalem ( Site 0902)
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center ( Site 0904)
  • Ramat Gan, Israel, 5265601
    • Sheba MC ( Site 0901)
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center ( Site 0900)
• Italy
  • Florence, Italy, 50134
    • Azienda Ospedaliero Universitaria Careggi ( Site 0955)
  • Milan, Italy, 20133
    • Istituto Nazionale Tumori ( Site 0950)
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia ( Site 0953)
  • Milan, Italy, 20142
    • Azienda Ospedaliera San Paolo ( Site 0952)
  • Napoli, Italy, 80121
    • Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0951)
  • Padua, Italy, 35128
    • Istituto Oncologico Veneto ( Site 0957)
  • Pavia, Italy, 27100
    • Fondazione IRCCS - Policlinico San Matteo ( Site 0960)
  • MO
    • Modena, MO, Italy, 41124
      • Azienda Ospedaliero Universitaria di Modena Policlinico ( Site 0954)
• Japan
  • Chiba, Japan, 260-8717
    • Chiba Cancer Center ( Site 0358)
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital ( Site 0352)
  • Osaka, Japan, 541-8567
    • Osaka International Cancer Institute ( Site 0355)
  • Tokyo, Japan, 113-8519
    • Medical Hospital, Tokyo Medical And Dental University ( Site 0356)
  • Tokyo, Japan, 135-8550
    • The Cancer Institute Hospital of JFCR ( Site 0357)
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East ( Site 0350)
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Hokkaido University Hospital ( Site 0351)
  • Hyōgo
    • Akashi, Hyōgo, Japan, 673-8558
      • Hyogo Cancer Center ( Site 0354)
  • Kagawa-ken
    • Kita-gun, Kagawa-ken, Japan, 761-0793
      • Kagawa University Hospital ( Site 0359)
  • Miyagi
    • Natori-shi, Miyagi, Japan, 981-1293
      • Miyagi Cancer Center ( Site 0353)
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Noordwest Ziekenhuisgroep NWZ ( Site 1350)
  • Amsterdam, Netherlands, 1081 HV
    • VU Medisch Centrum ( Site 1352)
  • Groningen, Netherlands, 9713 GZ
    • UMCG ( Site 1351)
  • Nijmegen, Netherlands, 6525 GA
    • UMC St. Radboud ( Site 1356)
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus University Medical Center ( Site 1354)
• New Zealand
  • Newtown
    • Wellington, Newtown, New Zealand, 6021
      • Capital & Coast District Health Board - Wellington Hospital ( Site 0400)
• Poland
  • Bielsko-Biala, Poland, 43-300
    • Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 1005)
  • Gdynia, Poland, 81-519
    • Szpital Morski im. PCK. Szpitale Pomorskie Sp. Z o.o ( Site 1007)
  • Gliwice, Poland, 44-101
    • Centrum Onkologii. Instytut im. Marii Sklodowskiej-Curie ( Site 1010)
  • Krakow, Poland, 31-826
    • Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 1008)
  • Szczecin, Poland, 71-730
    • Zachodniopomorskie Centrum Onkologii ( Site 1013)
  • Warsaw, Poland, 02-781
    • Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 1000)
  • Lower Silesian Voivodeship
    • Wroclaw, Lower Silesian Voivodeship, Poland, 53-413
      • Dolnoslaskie Centrum Onkologii. ( Site 1001)
  • Masovian Voivodeship
    • Wieliszew, Masovian Voivodeship, Poland, 05-135
      • Mazowiecki Szpital Onkologiczny ( Site 1015)
• South Korea
  • Daejeon, South Korea, 35015
    • Chungnam National University Hospital ( Site 0455)
  • Seoul, South Korea, 03722
    • Severance Hospital Yonsei University Health System ( Site 0452)
  • Seoul, South Korea, 06351
    • Samsung Medical Center ( Site 0450)
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital ( Site 0453)
  • North Chungcheong
    • Cheongju-si, North Chungcheong, South Korea, 28644
      • Chungbuk National University Hospital ( Site 0454)
• Spain
  • Barcelona, Spain, 08035
    • H.U. Vall de Hebron ( Site 1052)
  • L'Hospitalet de Llobregat, Spain, 08907
    • Hospital Duran i Reynals ( Site 1053)
  • Madrid, Spain, 28024
    • Hospital Doce de Octubre ( Site 1054)
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal ( Site 1055)
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos ( Site 1051)
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria ( Site 1056)
  • Valencia, Spain, 46014
    • Hospital Gral Universitario de Valencia ( Site 1050)
• Taiwan
  • Kaohsiung City, Taiwan, 83301
    • Chang Gung Medical Foundation - Kaohsiung ( Site 0501)
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital ( Site 0506)
  • Tainan, Taiwan, 70403
    • National Cheng Kung University Hospital ( Site 0503)
  • Taipei, Taiwan, 10048
    • National Taiwan University Hospital ( Site 0500)
  • Taipei, Taiwan, 105
    • MacKay Memorial Hospital ( Site 0505)
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital ( Site 0504)
  • Taoyuan District, Taiwan, 333
    • Linkou Chang Gung Memorial Hospital ( Site 0502)
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01250
    • Basken Adana Dr.Turgut Noyan Uygulama ve Arastirma Merkezi ( Site 1103)
  • Ankara, Turkey (Türkiye), 06100
    • Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1102)
  • Ankara, Turkey (Türkiye), 06800
    • Ankara Sehir Hastanesi ( Site 1108)
  • Istanbul, Turkey (Türkiye), 34093
    • Istanbul Universitesi Istanbul Tip Fakultesi ( Site 1100)
  • Istanbul, Turkey (Türkiye), 34214
    • Medipol Universite Hastanesi ( Site 1104)
  • Izmir, Turkey (Türkiye), 35520
    • Medical Park Izmir Hastanesi ( Site 1109)
  • Kocaeli, Turkey (Türkiye), 41380
    • Kocaeli Universitesi Tip Fakultesi ( Site 1106)
  • Malatya, Turkey (Türkiye), 44280
    • Inonu Universitesi Tip Fakultesi ( Site 1101)
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • St Bartholomew s Hospital ( Site 1205)
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden Foundation Trust ( Site 1200)
  • London, United Kingdom, W6 8RF
    • Imperial Healthcare NHS Trust Charing Cross Hospital ( Site 1204)
  • Preston, United Kingdom, PR2 9HT
    • Lancashire Teaching Hospitals NHS Foundation Trust ( Site 1208)
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Foundation Trust ( Site 1203)
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden NHS Foundation Trust ( Site 1201)
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk & Norwich University Hospital NHS Foundation Trust ( Site 1206)
  • Staffordshire
    • Stoke-on-Trent, Staffordshire, United Kingdom, ST4 6QG
      • University Hospital of North Staffordshire ( Site 1202)
  • Suffolk
    • Ipswich, Suffolk, United Kingdom, IP4 5PD
      • Ipswich Hospital ( Site 1207)
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center ( Site 0273)
    • San Francisco, California, United States, 94115
      • University of California San Francisco ( Site 0274)
    • Santa Rosa, California, United States, 95403
      • St. Joseph Heritage Healthcare ( Site 0254)
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Hospital at Yale New Haven ( Site 0256)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center ( Site 0260)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University ( Site 0264)
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital ( Site 0281)
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center ( Site 0285)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital and Health Systems ( Site 0267)
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute ( Site 0272)
  • Missouri
    • Springfield, Missouri, United States, 65804
      • Mercy Clinic Cancer and Hematology - Chub O'Reilly Cancer Center ( Site 0290)
  • Montana
    • Billings, Montana, United States, 59102
      • St. Vincent Healthcare Frontier Cancer Center ( Site 0286)
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada ( Site 8004)
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester - James P. Wilmot Cancer Center ( Site 0255)
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care, Inc. ( Site 8003)
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Willamette Valley Cancer Institute and Research Center ( Site 8000)
  • Pennsylvania
    • Easton, Pennsylvania, United States, 18045
      • St. Luke's Cancer Center - Anderson ( Site 0251)
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • St. Francis Hospital Cancer Center ( Site 1461)
  • Texas
    • Arlington, Texas, United States, 76014
      • Texas Oncology-Arlington North ( Site 8005)
    • Austin, Texas, United States, 78731
      • Texas Oncology-Austin Central ( Site 8002)
    • Longview, Texas, United States, 75601
      • Texas Oncology PA ( Site 8001)
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System ( Site 0261)
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance/Univ of Washington Medical Center ( Site 0269)
    • Spokane, Washington, United States, 99208
      • Medical Oncology Associates (Summit Cancer Centers) ( Site 0257)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has a pathologically proven new diagnosis of oropharyngeal p16 positive, oropharyngeal p16 negative, or larynx/hypopharynx/oral cavity (independent of p16) squamous cell carcinoma. Participants with oral cavity tumors need to have unresectable disease. Participants with multiple synchronous tumors are not eligible for the study.
• 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:

• Is currently participating or has participated in a study with an investigational agent or using an investigational device within 4 weeks of the first dose of study therapy
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Biological: Pembrolizumab; Administered as an intravenous (IV) infusion every 3 weeks (Q3W); Other Names: KEYTRUDA®; Drug: Cisplatin; 100 mg/m^2 administered as an IV infusion Q3W; Other Names: Platinol®; Platinol®-AQ; Radiation: Accelerated Fractionation (AFX) Radiotherapy; 70 Gray (Gy) given in 35 fractions over 6 weeks; Radiation: Standard Fractionation (SFX) Radiotherapy; 70 Gy given in 35 fractions over 7 weeks
Placebo Comparator: 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.	Drug: Cisplatin; 100 mg/m^2 administered as an IV infusion Q3W; Other Names: Platinol®; Platinol®-AQ; Radiation: Accelerated Fractionation (AFX) Radiotherapy; 70 Gray (Gy) given in 35 fractions over 6 weeks; Radiation: Standard Fractionation (SFX) Radiotherapy; 70 Gy given in 35 fractions over 7 weeks; Drug: Placebo; Normal saline or dextrose solution administered as an IV infusion Q3W

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free Survival (EFS)	EFS was defined as the time from date of randomization to the date of first record of any of the following events: death due to any cause; progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) or biopsy as indicated for locoregional progression or recurrence or distant metastasis. As well as the first record of the following types of surgery: salvage surgery for persistent or residual disease at the primary tumor site requiring surgical removal when invasive cancer is present on final pathology; neck dissection or surgery (performed for clinical or radiological disease progression per RECIST 1.1) ≤ 20 weeks from end of CRT when invasive cancer is present; or neck dissection or surgery >20 weeks from end of CRT when invasive cancer is present. The non-parametric Kaplan-Meier method was used to estimate the EFS curve in each treatment group.	Up to approximately 62 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of analysis were censored at the date the participant was last known to be alive. The non-parametric Kaplan-Meier method was used to estimate the survival curve in each treatment group.	Up to approximately 62 months
Number of Participants Who Experienced an Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. An AE is any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. The number of participants who experienced an AE is presented.	Up to approximately 88 months
Number of Participants Who Discontinued Study Drug Due to an AE	An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. An AE is any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. The number of participants who discontinued study drug due to an AE is presented.	Up to approximately 15 months
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status (Item 29) Score	The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life (QoL) of cancer patients. For Global Health Status (GHS) (Item 29), participants are asked "How would you rate your overall health during the past week?" Individual items are scored on a 7-point (1=very poor to 7=excellent). Raw scores for each scale are standardized into a range of 0 to 100 by linear transformation, with a higher score indicating a better level of function and better overall GHS. A change from baseline of 10 points on the 100-point EORTC QLQ-C30 scale is considered as clinically relevant. Analysis based on a constrained longitudinal data analysis (cLDA) model with the patient reported outcomes (PRO) scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of human papilloma virus (HPV) status and overall cancer stage.	Baseline and up to week 45
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck Questionnaire (EORTC QLQ-H&N35) Swallowing Score	EORTC QLQ Head and Neck Questionnaire (H&N35) measures QoL in head and neck cancer (HNC) patients. It consists of 7 multi-item scales (pain in the mouth, problems with swallowing, senses, speech, social eating, social contact, and sexuality). Participant responses to the swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Change from baseline in swallowing was measured. A change from baseline of 10 points on the 100-point EORTC QLQ-H&N35 is considered as clinically relevant. Analysis based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.	Baseline and up to Week 45
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck Questionnaire (EORTC QLQ-H&N35) Speech Score	EORTC QLQ Head and Neck Questionnaire (H&N35) measures QoL in head and neck cancer (HNC) patients. It consists of 7 multi-item scales (pain in the mouth, problems with swallowing, senses, speech, social eating, social contact, and sexuality). Participant responses to the speech scale (Items 30-32) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Change from baseline in speech was measured. A change from baseline of 10 points on the 100-point EORTC QLQ-H&N35 is considered as clinically relevant. Analysis based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.	Baseline and up to Week 45
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck Questionnaire (EORTC QLQ-H&N35) Pain Symptom Score	EORTC QLQ Head and Neck Questionnaire (H&N35) measures QoL in head and Neck Cancer (HNC) patients. It consists of 7 multi-item scales (pain in the mouth, problems with swallowing, senses, speech, social eating, social contact, and sexuality). Participant responses to the pain scale (Items 31-34) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Change from baseline in pain symptoms was measured. A change from baseline of 10 points on the 100-point EORTC QLQ-H&N35 is considered as clinically relevant. Analysis based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.	Baseline and up to Week 45
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Functioning Score	The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life (QoL) of cancer patients. Participant responded to 5 questions from the EORTC QLQ-C30 about their physical functioning scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100, where a higher score indicates a better physical functioning. A change from baseline of 10 points on the 100-point scale is considered as clinically relevant. Analysis was based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage.	Baseline and up to Week 45

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Merck Clinical Trial Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2017
• Primary Completion (Actual): May 31, 2022
• Study Completion (Actual): August 21, 2024

Study Registration Dates

• First Submitted: February 1, 2017
• First Submitted That Met QC Criteria: February 1, 2017
• First Posted (Estimated): February 2, 2017

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: PD-1; PD-L1; PD1; PDL1; Head and Neck Squamous Cell Carcinoma; Programmed Cell Death Receptor 1 (PD-1); Programmed Cell Death Receptor Ligand 1 (PD-L1); Programmed Cell Death Receptor Ligand 2 (PD-L2); PDL2
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body; Therapeutics; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds; Cisplatin; Radiotherapy; pembrolizumab
• Other Study ID Numbers: 3475-412; MK-3475-412 (Other Identifier: MSD); 173640 (Registry Identifier: JAPIC-CTI); KEYNOTE-412 (Other Identifier: MSD); 2016-003934-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No