Clinical trial NCT03040999: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Head and Neck Neoplasms
Keywords: 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)
PD1
PD-1
PDL1
PD-L1
PDL2
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-02-02
Enrollment: 804
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Event-free Survival (EFS)
timeFrame: Up to approximately 62 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 62 months
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From time of first dose of study treatment until 90 days after last dose (up to approximately 19 months)
measure: Number of Participants Discontinuing Study Drug Due to an AE
timeFrame: From time of first dose of study treatment until the end of treatment (up to approximately 16 months)
measure: Change From Baseline in Global Health Status/Quality of Life (GHS/QoL)
timeFrame: Prior to the first dose of study treatment (Baseline) and up to Week 45
measure: Change From Baseline in Swallowing, Speech, and Pain Symptoms
timeFrame: Prior to the first dose of study treatment (Baseline) and up to Week 45
measure: Change From Baseline in Physical Functioning
timeFrame: Prior to the first dose of study treatment (Baseline) and up to Week 45
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center ( Site 0273)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco ( Site 0274)
state: California
city: Santa Rosa
country: United States
facility: St. Joseph Heritage Healthcare ( Site 0254)
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale New Haven ( Site 0256)
state: Connecticut
city: Chicago
country: United States
facility: Rush University Medical Center ( Site 0260)
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University ( Site 0264)
state: Indiana
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center at St. Tammany Parish Hospital ( Site 0281)
state: Louisiana
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center ( Site 0285)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital and Health Systems ( Site 0267)
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute ( Site 0272)
state: Michigan
city: Springfield
country: United States
facility: Mercy Clinic Cancer and Hematology - Chub O'Reilly Cancer Center ( Site 0290)
state: Missouri
city: Billings
country: United States
facility: St. Vincent Healthcare Frontier Cancer Center ( Site 0286)
state: Montana
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada ( Site 8004)
state: Nevada
city: Rochester
country: United States
facility: University of Rochester - James P. Wilmot Cancer Center ( Site 0255)
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc. ( Site 8003)
state: Ohio
city: Eugene
country: United States
facility: Willamette Valley Cancer Institute and Research Center ( Site 8000)
state: Oregon
city: Easton
country: United States
facility: St. Luke's Cancer Center - Anderson ( Site 0251)
state: Pennsylvania
city: Greenville
country: United States
facility: St. Francis Hospital Cancer Center ( Site 1461)
state: South Carolina
city: Arlington
country: United States
facility: Texas Oncology-Arlington North ( Site 8005)
state: Texas
city: Austin
country: United States
facility: Texas Oncology-Austin Central ( Site 8002)
state: Texas
city: Longview
country: United States
facility: Texas Oncology PA ( Site 8001)
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System ( Site 0261)
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance/Univ of Washington Medical Center ( Site 0269)
state: Washington
city: Spokane
country: United States
facility: Medical Oncology Associates (Summit Cancer Centers) ( Site 0257)
state: Washington
city: Liverpool
country: Australia
facility: Liverpool Hospital ( Site 0301)
state: New South Wales (Australia)
city: Blacktown
country: Australia
facility: Blacktown Hospital Western Sydney Local Health District ( Site 0304)
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital ( Site 0305)
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women s Hospital ( Site 0302)
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital ( Site 0303)
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre ( Site 0300)
state: Victoria
city: Graz
country: Austria
facility: Landeskrankenhaus - Universitatsklinikum Graz ( Site 0601)
city: Linz
country: Austria
facility: Krankenhaus der Barmherzigen Schwestern Linz ( Site 0603)
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg ( Site 0600)
city: Vienna/Wien
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien ( Site 0602)
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc - Bruxelles ( Site 0651)
city: Gent
country: Belgium
facility: UZ Gent ( Site 0650)
city: Leuven
country: Belgium
facility: UZ Leuven Campus Gasthuisberg ( Site 0652)
city: Liege
country: Belgium
facility: C.H.U. Sart Tilman-Service d'Oncologie Medicale ( Site 0654)
city: Namur
country: Belgium
facility: Clinique et Maternite Sainte-Elisabeth ( Site 0653)
city: Salvador
country: Brazil
facility: Hospital Santa Izabel - Santa Casa de Misericordia da Bahia ( Site 0006)
state: Bahia
city: Fortaleza
country: Brazil
facility: Centro Regional Integrado de Oncologia ( Site 0002)
state: Ceara
city: Natal
country: Brazil
facility: Liga Norte Riograndense Contra o Cancer ( Site 0005)
state: Rio Grande Do Norte
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao ( Site 0001)
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre ( Site 0011)
state: RS
city: Barretos
country: Brazil
facility: Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 0003)
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer de Sao Paulo - ICESP ( Site 0004)
state: SP
city: Ribeirao Preto
country: Brazil
facility: Hospital das Clinicas da FMUSP de Ribeirao Preto ( Site 0008)
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0010)
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre ( Site 0063)
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute ( Site 0064)
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre ( Site 0062)
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre ( Site 0055)
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Cancer Care ( Site 0052)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0051)
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre ( Site 0061)
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0057)
state: Quebec
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe ( Site 0151)
state: Antioquia
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0150)
state: Valle Del Cauca
city: Cali
country: Colombia
facility: Centro Medico Imbanaco de Cali S.A ( Site 0156)
state: Valle Del Cauca
city: Bogota
country: Colombia
facility: Centro de Investigacion Clinica del Country ( Site 0155)
city: Brno
country: Czechia
facility: FN Brno. ( Site 0703)
city: Hradec Kralove
country: Czechia
facility: Fakultni Nemocnice Hradec Kralove ( Site 0705)
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc ( Site 0701)
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava ( Site 0702)
city: Praha 8
country: Czechia
facility: Nemocnice Na Bulovce ( Site 0700)
city: Praha
country: Czechia
facility: 2. LF UK a FN Motol ( Site 0704)
city: Le Mans
country: France
facility: Centre Jean Bernard Laboratoire Mahe Meziani ( Site 0760)
city: Limoges
country: France
facility: Clinique Francois Chenieux ( Site 0757)
city: Toulouse Cedex 09
country: France
facility: Institut Claudius Regaud ( Site 0754)
city: Vandoeuvre les Nancy
country: France
facility: Institut De Cancerologie De Lorraine ( Site 0758)
city: Villejuif
country: France
facility: Institut Gustave Roussy ( Site 0759)
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen ( Site 0801)
city: Gera
country: Germany
facility: SRH Waldklinikum Gera GmbH ( Site 0802)
city: Hamburg
country: Germany
facility: Universitares Cancer Center Hamburg - UCCH ( Site 0811)
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover ( Site 0807)
city: Luebeck
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein-Campus Luebeck ( Site 0803)
city: Munchen
country: Germany
facility: Klinikum der Universitaet Munchen ( Site 0810)
city: Ulm
country: Germany
facility: Universitaetsklinik Ulm ( Site 0804)
city: Haifa
country: Israel
facility: Rambam MC ( Site 0903)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Jerusalem ( Site 0902)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center ( Site 0904)
city: Ramat Gan
country: Israel
facility: Sheba MC ( Site 0901)
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center ( Site 0900)
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria di Modena Policlinico ( Site 0954)
state: MO
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi ( Site 0955)
city: Milano
country: Italy
facility: Istituto Nazionale Tumori ( Site 0950)
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia ( Site 0953)
city: Milano
country: Italy
facility: Azienda Ospedaliera San Paolo ( Site 0952)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0951)
city: Padova
country: Italy
facility: Istituto Oncologico Veneto ( Site 0957)
city: Pavia
country: Italy
facility: Fondazione IRCCS - Policlinico San Matteo ( Site 0960)
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East ( Site 0350)
state: Chiba
city: Sapporo
country: Japan
facility: Hokkaido University Hospital ( Site 0351)
state: Hokkaido
city: Akashi
country: Japan
facility: Hyogo Cancer Center ( Site 0354)
state: Hyogo
city: Kita-gun
country: Japan
facility: Kagawa University Hospital ( Site 0359)
state: Kagawa
city: Natori
country: Japan
facility: Miyagi Cancer Center ( Site 0353)
state: Miyagi
city: Chiba
country: Japan
facility: Chiba Cancer Center ( Site 0358)
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital ( Site 0352)
city: Osaka
country: Japan
facility: Osaka International Cancer Institute ( Site 0355)
city: Tokyo
country: Japan
facility: Medical Hospital, Tokyo Medical And Dental University ( Site 0356)
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR ( Site 0357)
city: Cheongju si
country: Korea, Republic of
facility: Chungbuk National University Hospital ( Site 0454)
state: Chungcheongbuk Do
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital ( Site 0453)
state: Gyeonggi-do
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital ( Site 0455)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0452)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 0450)
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep NWZ ( Site 1350)
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum ( Site 1352)
city: Groningen
country: Netherlands
facility: UMCG ( Site 1351)
city: Nijmegen
country: Netherlands
facility: UMC St. Radboud ( Site 1356)
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center ( Site 1354)
city: Wellington
country: New Zealand
facility: Capital & Coast District Health Board - Wellington Hospital ( Site 0400)
state: Newtown
city: Wroclaw
country: Poland
facility: Dolnoslaskie Centrum Onkologii. ( Site 1001)
state: Dolnoslaskie
city: Wieliszew
country: Poland
facility: Mazowiecki Szpital Onkologiczny ( Site 1015)
state: Mazowieckie
city: Bielsko-Biala
country: Poland
facility: Beskidzkie Centrum Onkologii im. Jana Pawla II ( Site 1005)
city: Gdynia
country: Poland
facility: Szpital Morski im. PCK. Szpitale Pomorskie Sp. Z o.o ( Site 1007)
city: Gliwice
country: Poland
facility: Centrum Onkologii. Instytut im. Marii Sklodowskiej-Curie ( Site 1010)
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 1008)
city: Szczecin
country: Poland
facility: Zachodniopomorskie Centrum Onkologii ( Site 1013)
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie ( Site 1000)
city: Barcelona
country: Spain
facility: H.U. Vall de Hebron ( Site 1052)
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals ( Site 1053)
city: Madrid
country: Spain
facility: Hospital Doce de Octubre ( Site 1054)
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal ( Site 1055)
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos ( Site 1051)
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria ( Site 1056)
city: Valencia
country: Spain
facility: Hospital Gral Universitario de Valencia ( Site 1050)
city: Kaohsiung
country: Taiwan
facility: Chang Gung Medical Foundation - Kaohsiung ( Site 0501)
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital ( Site 0506)
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital ( Site 0503)
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital ( Site 0500)
city: Taipei
country: Taiwan
facility: MacKay Memorial Hospital ( Site 0505)
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital ( Site 0504)
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital ( Site 0502)
city: Adana
country: Turkey
facility: Basken Adana Dr.Turgut Noyan Uygulama ve Arastirma Merkezi ( Site 1103)
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1102)
city: Ankara
country: Turkey
facility: Ankara Sehir Hastanesi ( Site 1108)
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi ( Site 1100)
city: Istanbul
country: Turkey
facility: Medipol Universite Hastanesi ( Site 1104)
city: Izmir
country: Turkey
facility: Medical Park Izmir Hastanesi ( Site 1109)
city: Kocaeli
country: Turkey
facility: Kocaeli Universitesi Tip Fakultesi ( Site 1106)
city: Malatya
country: Turkey
facility: Inonu Universitesi Tip Fakultesi ( Site 1101)
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital NHS Foundation Trust ( Site 1206)
state: Norfolk
city: Stoke-On-Trent
country: United Kingdom
facility: University Hospital of North Staffordshire ( Site 1202)
state: Staffordshire
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital ( Site 1207)
state: Suffolk
city: London
country: United Kingdom
facility: St Bartholomew s Hospital ( Site 1205)
city: London
country: United Kingdom
facility: The Royal Marsden Foundation Trust ( Site 1200)
city: London
country: United Kingdom
facility: Imperial Healthcare NHS Trust Charing Cross Hospital ( Site 1204)
city: Preston
country: United Kingdom
facility: Lancashire Teaching Hospitals NHS Foundation Trust ( Site 1208)
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust ( Site 1203)
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust ( Site 1201)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.