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    Summary
    EudraCT Number:2017-001139-38
    Sponsor's Protocol Code Number:MK-3475-689
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2017-11-22
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-001139-38
    A.3Full title of the trial
    A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for StageIII-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)
    Estudio de fase III, aleatorizado y abierto para evaluar pembrolizumab
    como tratamiento neoadyuvante y en combinación con la asistencia habitual como tratamiento adyuvante en el carcinoma epidermoide de cabeza y cuello locorregionalmente avanzado (CECC LA), extirpable, en estadio III-IVA.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MK-3475 (SCH 9000475) as neoadjuvant and adjuvant therapy in Stage III-IVA resectable LA HNSCC (Locoregionally Advanced Head and Neck Squamous Cell Carcinoma)
    MK-3475 (SCH 9000475) como tratamiento neoadyuvante y adyuvante en el CECC LA resecable en estadio III-IVA
    A.3.2Name or abbreviated title of the trial where available
    MK-3475 (SCH 9000475) as neoadjuvant and adjuvant therapy in Stage III-IVA resectable LA HNSCC
    MK-3475 (SCH 9000475) como tratamiento neoadyuvante y adyuvante en el CECC LA
    A.4.1Sponsor's protocol code numberMK-3475-689
    A.5.4Other Identifiers
    Name:IND NUMBERNumber:122,325
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España S.A.
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34913210590
    B.5.6E-mailensayos_clinicos@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin Accord
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare S.L.U.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin Teva
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCISPLATIN
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)
    carcinoma epidermoide de cabeza y cuello locorregionalmente avanzado (CECC LA), extirpable , en estadio III-IVA
    E.1.1.1Medical condition in easily understood language
    Newly diagnosed, resectable Stage III-IVA locally advanced Head and Neck Squamous Cell Carcinoma subjects
    Diagnostico reciente de Cáncer de Cabeza y Cuello Epidermoide Localmente Avanzado, extirpable, en estadio III-IVA
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To compare the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery between participants who receive neoadjuvant therapy with pembrolizumab and participants who do not.
    2. To compare the event-free survival (EFS) as assessed by blinded independent central review (BICR) between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with radiotherapy (RT) ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy.
    1.Comparar la tasa de respuesta anatomopatológica importante (RAPi), evaluada por el anatomopatólogo central en el momento de la cirugía definitiva, entre los participantes que reciban tratamiento neoadyuvante con pembrolizumab y los que no lo hagan.
    2.Comparar la SSE, evaluada mediante una RCIE, entre los participantes que reciban tratamiento neoadyuvante con pembrolizumab y pembrolizumab con RT ± cisplatino como tratamiento adyuvante y los que solo reciban RT ± cisplatino como tratamiento adyuvante.
    E.2.2Secondary objectives of the trial
    1. To compare overall survival (OS) between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with RT ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy.
    2. To evaluate the rate of pathological complete response (pCR) as assessed by the central pathologist at the time of definitive surgery.
    3. To evaluate global health status/quality of life (QoL) scores using the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, and swallowing, speech and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQH&N35).
    4. To determine the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy.
    1.Comparar la SG entre los participantes que reciban tratamiento neoadyuvante con pembrolizumab y pembrolizumab con RT ± cisplatino como tratamiento adyuvante y los que solo reciban RT ± cisplatino como tratamiento adyuvante.
    2.Evaluar la tasa de respuesta completa anatomopatológica (RCap) evaluada por el anatomopatólogo central en el momento de la cirugía definitiva.
    3.Evaluar puntuaciones de estado de salud general/calidad de vida mediante el cuestionario de calidad de vida de la Organización Europea para la Investigación y el Tratamiento del Cáncer (QLQ)-C30, así como puntuaciones de síntomas relacionados con la deglución, el habla y dolor mediante el cuestionario de calidad de vida específico de la cabeza y el cuello (QLQ-H&N35) de la EORTC.
    4.Determinar la seguridad y la tolerabilidad de pembrolizumab como tratamiento neoadyuvante y en combinación con RT ± cisplatino como tratamiento adyuvante.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    Meck llevará a cabo investigaciones biomédicas futuras con las muestras obtenidas de forma sistemática y específica durante este ensayo clínico.
    Estas investigaciones tendrán por objeto el análisis de biomarcadores para abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en
    muestras de los sujetos que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigación biomédica futura consiste en estudiar e identificar
    biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal
    información para desarrollar vacunas y fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco o la vacuna adecuados en el momento preciso.
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all of the following criteria apply:
    1. Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma as assessed by the investigator based on baseline imaging and clinical assessment that is either:
    a. Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0
    OR
    b. Stage III or IVA oropharyngeal p16 negative
    OR
    c. Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16).
    2. Be eligible for primary surgery based on investigator decision and per local practice.
    3. Male/female participants who are at least 18 years of age on the day of signing informed consent
    4. A male participant must agree to use a contraception during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.
    5. A female participant is eligible to participate if she is not pregnant, not
    breastfeeding, and at least one of the following conditions applies:
    a.) Not a woman of childbearing potential (WOCBP) OR
    b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment.
    6. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main study without participating in Future Biomedical Research.
    7. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator/radiology.
    8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate). Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
    9. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using ‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells. If HPV status was previously tested using this method, no additional testing is required.
    10. Have an ECOG performance status of 0 to 1 performed within 10 days of treatment initiation.
    11. Have adequate organ function, as defined. Specimens must be collected within 10 days prior to the start of study treatment.
    Únicamente podrán ser incluidos en el estudio los participantes que cumplan todos los criterios siguientes:
    1. Diagnóstico reciente, confirmado histológicamente, de carcinoma epidermoide extirpable, no metastásico, según lo determinado por el investigador basándose en la evaluación de imagen y clínica basal, que se corresponda con uno de los siguientes:
    a. De bucofaringe en estadio III con p16 positivo, que sea T4 (N0-N2), M0 O
    b. De bucofaringe en estadio III o IVA con p16 negativo O
    c. De laringe, hipofaringe o cavidad bucal en estadio III o IVA (independientemente de la expresión de p16).
    2. Elegibilidad para cirugía primaria según la decisión del investigador y conforme a la práctica local.
    3. Participante de cualquier sexo con una edad mínima de 18 años el día de firma del consentimiento informado.
    4. Los varones deben comprometerse a utilizar métodos anticonceptivos de este protocolo durante el período de tratamiento y hasta, como mínimo, 180 días después de la última dosis del tratamiento del estudio, así como a abstenerse de donar semen durante este período.
    5. Podrá participar toda mujer que no esté embarazada ni dando el pecho y que cumpla al menos una de las condiciones siguientes: a.) No es una mujer en edad fértil (MEF)
    b.) Es una MEF que se compromete a seguir las recomendaciones sobre métodos anticonceptivos, durante el período de tratamiento y hasta, como mínimo, 180 días después de la última dosis del tratamiento del estudio.
    6. El participante (o su representante legal cuando proceda) otorga su consentimiento informado por escrito para el estudio. El participante también podrá otorgar su consentimiento para las investigaciones biomédicas futuras. No obstante, podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    7. Carga tumoral evaluable (lesiones tumorales mensurables y/o no mensurables) determinada mediante tomografía computarizada (TC) o resonancia magnética (RM), conforme a los criterios RECIST 1.1, por el investigador o el radiólogo del centro local.
    8. Donación de una muestra de tejido tumoral de archivo o una biopsia con aguja gruesa o por escisión de obtención reciente de una lesión tumoral no irradiada previamente para realizar un análisis del biomarcador PD-L1 a partir de una biopsia con aguja gruesa o por escisión (no se considera adecuada una aspiración con aguja fina [AAF]).Se prefiere el uso de bloques de tejido fijados en formol e incluidos en parafina a las extensiones. Se prefiere el uso de biopsias recientes al tejido de archivo.
    9. Disponibilidad de los resultados de un análisis (local) del estado del VPH en relación con el cáncer de bucofaringe, definido como un análisis IHQ de p16 utilizando el ensayo histológico de p16 CINtec® (Ventana Medical Systems Inc., Tucson AZ), el aparato de autotinción “Benchmark Ultra’ (Ventana, Tucson, AZ) y el protocolo habitual. La expresión de p16 positiva se define como una tinción intensa y difusa del núcleo y el
    citoplasma del 70 % o más de las células del tumor. En caso de que se hayan realizado previamente análisis del estado del VPH utilizando este procedimiento, no será necesario repetirlos.
    10. Estado funcional del ECOG de 0 o 1 evaluado en los 10 días previos al comienzo del tratamiento.
    11. Presencia de una función orgánica adecuada. Las muestras se obtendrán en los 10 días previos al comienzo del tratamiento del estudio.
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:
    1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.
    2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
    3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or within 24 hours prior to the start of RT ± cisplatin. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
    4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
    5. Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to randomization/allocation.
    6. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
    7. 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.
    8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
    9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
    10. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review.
    11. Has Grade ≥2 audiometric hearing loss.
    12. Has Grade ≥2 neuropathy.
    13. Has Grade 3-4 bleeding due to the underlying malignancy.
    14. If participant has received major surgery, and the participant has not recovered adequately from the toxicity and/or complications from the intervention prior to randomization.
    15. Has had previous allogeneic tissue/solid organ transplant.
    16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, RT or cisplatin or their analogs.
    17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
    18. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    19. Has an active infection requiring systemic therapy.
    20. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
    21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] RNA [qualitative] is detected).
    22. 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.
    23. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
    24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.
    Quedará excluido del ensayo todo participante que cumpla alguno de los criterios siguientes:
    1. Presencia de un CECC LA en estadio T4B y/o N3 y/o de metástasis a distancia.
    2. Presencia de un cáncer en una localización distinta de la bucofaringe, la laringe y la hipofaringe o la cavidad bucal, como CCC nasofaríngeos, sinusales, paranasales u otros CCC primarios desconocidos.
    3. MEF con prueba de embarazo en orina positiva en las 72 horas previas a la aleatorización o en las 24 horas previas al inicio de la RT ± cisplatino. Cuando el resultado de la prueba en orina sea positivo o no pueda confirmarse que es negativo, será necesario hacer una prueba de embarazo en suero.En tal caso, la participante será excluida si el resultado de la prueba de embarazo en suero es positivo.
    4. Tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T coinhibidor (como CTLA-4, OX- 40 o CD137).
    5. Tratamiento previo con radioterapia o antineoplásicos sistémicos, incluidos fármacos en investigación, contra el CCC en estudio antes de la aleatorización o asignación.
    6. Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del fármaco del estudio.Algunos ejemplos de este tipo de vacunas son los siguientes: sarampión, parotiditis, rubéola, varicela/zóster, fiebre amarilla, rabia, bacilo de Calmette-Guérin (BCG) y fiebre tifoidea.Las vacunas inyectables contra la gripe estacional contienen, por lo general, virus muertos y están permitidas; en cambio, las vacunas antigripales intranasales (por ejemplo, FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
    7. Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis del tratamiento del estudio.
    8. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico con esteroides (en dosis superiores a 10 mg diarios de prednisona o un equivalente) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis del fármaco del estudio.
    9. Presencia de otra neoplasia maligna conocida que está en progresión o que ha necesitado tratamiento activo en los últimos tres años.
    10. Presencia de metástasis radiológicamente detectables (aunque sean asintomáticas y/o hayan sido tratadas previamente) en el sistema nervioso central (SNC) y/o de meningitis carcinomatosa, según lo evaluado por el investigador del centro y la revisión radiológica.
    11. Hipoacusia audiométrica de grado ≥ 2.
    12. Presencia de una neuropatía de grado ≥ 2.
    13. Presencia de una hemorragia de grado 3-4 debida a la neoplasia maligna subyacente.
    14. El participante se ha sometido a una intervención de cirugía mayor y no se ha recuperado debidamente de la toxicidad y/o las complicaciones de la intervención antes de la aleatorización.
    15. Recepción de un alotrasplante de órgano sólido o tejidos previo.
    16. Presencia de hipersensibilidad grave (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus, a la RT o a cisplatino o a sus análogos.
    17. Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años. El tratamiento de reposición (por ejemplo, tiroxina, insulina o corticoides en dosis fisiológicas por insuficiencia suprarrenal o hipofisaria) no se considera una forma de tratamiento sistémico y se permitirá su uso.
    18. Antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroideso presencia de una neumonitis activa.
    19. Presencia de una infección activa que precisa tratamiento sistémico.
    20. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH).No es necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
    21. Antecedentes o seropositividad para hepatitis B (reactividad para el antígeno de superficie del virus de la hepatitis B [HBsAg]) o hepatitis C activa (se detecta ARN del virus de la hepatitis C [VHC] [cualitativo]).
    22. Antecedentes o datos presentes de cualquier proceso, tratamiento o anomalía analítica que, en opinión del investigador responsable del tratamiento, podría confundir los resultados del estudio, dificultar la participación durante la totalidad del estudio o motivar que la participación no sea lo más conveniente para el participante.
    23. Presencia de un trastorno psiquiátrico o por abuso de sustancias que pueda dificultar el cumplimiento de los requisitos del estudio.
    24. Embarazo, período de lactancia o intención de concebir o engendrar un hijo durante el período previsto del estudio, desde la visita de selección hasta 180 días después de la última dosis del tratamiento del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    1. Major pathological response - defined as participant with ≤10% viable tumor in resected tumor tissue.
    2. Event-free survival (EFS) - defined as the time from the date of randomization to the date of first record of any of the following events: radiographic disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by BICR, local or distant recurrence (for participants who are disease free after surgery); death due to any cause.
    1. Tasa de Respuesta Anatomopatológica: definida como el hecho de que un participante presente ≤ 10 % de tumor viable en el tejido tumoral extirpado
    2. Supervivencia Sin Episodios: definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha del primer registro de cualquiera de los episodios siguientes: progresión radiológica de la enfermedad conforme a los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1, según la RCIE; recidiva local o a distancia (para tratamiento adyuvante)
    E.5.1.1Timepoint(s) of evaluation of this end point
    27 months and 36 months
    27 meses y 36 meses
    E.5.2Secondary end point(s)
    1. Overall survival - defined as time from randomization to death due to any cause.
    2. Pathological complete response - defined as participant having no viable tumor tissue within entirely submitted and evaluated gross lesions.
    3. Change from baseline in the QoL and symptom scores from the global health status/QoL scales (items 29 and 30) of the EORTC QLQ-C30, and the swallowing
    multi-item scale (items 35-38), speech multi-item scale (items 46, 53-54), and pain multi-item scale (items 31-34) of the EORTC QLQ-H&N35.
    4. Participant experiencing adverse events (AEs)
    5. Participant discontinuing study drug due to AEs
    1. Supervivencia Global definida como el tiempo transcurrido entre la aleatorización y la muerte por cualquier causa.
    2 Anatomopatológica definida como el hecho de que un participante no presente tejido tumoral viable en el seno de lesiones macroscópicas enviadas y evaluadas en su totalidad.
    3. Variación con respecto al momento basal de las puntuaciones de calidad de vida y síntomas mediante las escalas de estado de salud general/calidad de vida (apartados 29 y 30) del cuestionario QLQ-C30 de la EORTC y las escalas de varios apartados sobre la deglución (apartados 35-38), el habla (apartados 46, 53-54) y el dolor (apartados 31-34) del cuestionario QLQ-H&N35 de la EORTC
    4 Participantes que presenten acontecimientos adversos (AA)
    5. Participantes que suspendan el tratamiento con el fármaco del estudio por Acontencimiento Adverso.
    E.5.2.1Timepoint(s) of evaluation of this end point
    27, 36 and 48 months
    27 , 36 y 48 Meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Grupo Control: no recibirá terapia neoadyuvante
    Active control: no neadjuvant therapy
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    France
    Germany
    Hungary
    Israel
    Korea, Republic of
    Poland
    Portugal
    Russian Federation
    Spain
    Taiwan
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The overall study ends when the last participant completes the last study-related phone-call or visit, withdraws from the study or is lost to follow-up (i.e. the participant is unable to be contacted by the investigator).
    El estudio finaliza cuando el último paticipante complete la última llamada o visita relacionada con el estudio, retire el consentimiento o se pierda durante el seguimiento (es decir, el investigador no puede contactar al participante).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state21
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 184
    F.4.2.2In the whole clinical trial 600
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants who remain on study after treatment will receive on-study follow up until year five and thereafter every 3 months via phone for survival status.
    Los participantes que permanezcan en el estudio después de finalizar el tratamiento se hará un seguimiento en el estudio hasta el quinto año y, posteriormente, cada 3 meses mediante llamadas telefónicas para recoger datos de supervivencia
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-01-12
    P. End of Trial
    P.End of Trial StatusRestarted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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