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    Summary
    EudraCT Number:2019-003060-42
    Sponsor's Protocol Code Number:MK-1454-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-12-20
    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 number2019-003060-42
    A.3Full title of the trial
    A Phase 2 Study in First Line Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma to Evaluate Intratumoral MK-1454 in Combination with IV Pembrolizumab vs IV Pembrolizumab Monotherapy
    Estudio de fase 2 en el carcinoma epidermoide de cabeza y cuello recurrente, metastásico o irresecable, tratado en primera línea para evaluar MK-1454 intratumoral en combinación con pembrolizumab IV frente a pembrolizumab IV en monoterapia.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Study in 1L HNSCC of IT MK-1454 / MK-3475 IV vs MK-3475 IV
    Estudio de fase 2 en CECC en 1L de MK-1454 IT/MK-3475 IV frente a MK-3475 IV.
    A.3.2Name or abbreviated title of the trial where available
    Phase 2 Study in 1L HNSCC of IT MK-1454 / MK-3475 IV vs MK-3475 IV
    Estudio de fase 2 en CECC en 1L de MK-1454 IT/MK-3475 IV frente a MK-3475 IV.
    A.4.1Sponsor's protocol code numberMK-1454-002
    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 &
    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 SA
    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+3491321 06 00
    B.5.5Fax number+3491321 05 90
    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.3.9.4EV 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 KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 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.3.9.4EV 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: 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 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.3.2Product code MK-1454
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratumoral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMK-1454
    D.3.9.2Current sponsor codeMK-1454
    D.3.9.4EV Substance CodeSUB184461
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.0
    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
    Patients with metastatic or unresectable, recurrent HNSCC
    Paciente con CECC recurrente, metastásico o irresecable.
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic or unresectable, recurrent HNSCC
    Paciente con CECC recurrente, metastásico o irresecable.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    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 evaluate Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    Evaluar la tasa de respuesta objetiva (TRO) conforme a los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST 1.1), mediante una revisión central independiente y enmascarada RCIE.
    E.2.2Secondary objectives of the trial
    1. To evaluate Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    2. To evaluate Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    3. To evaluate Overall Survival (OS)
    4. To assess the safety and tolerability of study treatment
    1.Evaluar LA supervivencia sin progresión (SSP) conforme a los criterios RECIST 1.1 mediante una RCIE.
    2.Evaluar la duración de la respuesta (DR) conforme a los criterios RECIST 1.1 mediante una RCIE.
    3.Evaluar la supervivencia global (SG).
    4.Evaluar la seguridad y tolerabilidad de la intervención del estudio.
    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 DNA (Blood) 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 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.
    Merck realizará investigaciones biomédicas futuras con las muestras
    obtenidas (sangre) para tal finalidad durante este ensayo clínico. Estas
    investigaciones tendrán por objeto el análisis de biomarcadores con el
    fin de 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 pacientes que hayan otorgado el consentimiento
    correspondiente. El objetivo de la obtención de muestras para
    investigaciones biomédicas futuras es 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 fármacos más seguros y eficaces o para
    garantizar que los sujetos reciban la dosis correcta del fármaco en el
    momento preciso.
    E.3Principal inclusion criteria
    1. Has histologically or cytologically confirmed diagnosis of metastatic or unresectable,recurrent HNSCC that is considered incurable by local therapies.
    Has not had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to signing consent, if given as part of multimodal treatment for locally advanced disease, is allowed.
    The eligible primary tumor must be located in oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology).
    2. Has tumor PD-L1 expression of CPS ≥1.
    3. Has at least 1 measurable lesion which is amenable to injection. IT injection for cutaneous lesions may be performed via visual inspection. IT injection for subcutaneous lesions may be performed via ultrasound guidance or via palpation. This injectable lesion must be measurable and meet one of the following criteria:
    A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, or ≥1.5 cm in short axis for a nodal lesion in solid tumor subjects. The longest diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal lesions in solid tumor subjects.
    Multiple coalescing, superficial lesions which in aggregate have a longest diameter of ≥1 cm and ≤10 cm.
    4. Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
    5. Demonstrates adequate organ function
    6. Has results from testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point (please see the Procedures Manual for details). If HPV status was previously tested, then no additional testing is required.
    7. Is male or female, from 18 years to unlimited years of age inclusive, at the time of signing the informed consent.
    8. Male participants of reproductive potential must agree to use a highly effective method of contraception during sexual contact with females of childbearing potential starting with the first dose of study medication through 120 days after the last dose of study therapy.
    9. Female participants of childbearing potential must be willing to use a highly effective method of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after last dose of study medication . Participants of childbearing potential are those who have not been surgically sterilized or have not been free of menses for >1 year.
    10. Female participants of childbearing potential must have a negative urine or serum pregnancy test at screening and again within 72 hours prior to receiving the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the participant to be eligible.
    11. Has voluntarily agreed to participate by giving written informed consent. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.
    12. HIV-infected participants must meet these additional criteria:
    a) Have HIV-1 infection documented by using any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1). HIV-1 infection is to be confirmed by using a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA VL.
    b) Have well-controlled HIV on anti-retroviral therapy (ART), defined as:
    1) must have a CD4+ T-cell count >350 cells/mm3 at time of screening;
    2) must have achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 copies/mL or below the LLOQ (lowest
    limit of quantification) using the locally available assay at the time of screening and for at least 12 weeks prior to screening;
    3) must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).
    1. Diagnóstico confirmado histológica o citológicamente de CECC recurrente, irresecable o metastásico que se considere incurable con tratamientos locales.
    No haber recibido tratamiento sistémico previo en el contexto recurrente o metastásico. Se permite el tratamiento sistémico finalizado más de 6 meses antes de la firma del consentimiento, siempre que se haya administrado como parte de un tratamiento multimodal contra la enfermedad localmente avanzada.
    El tumor primario elegible deberá estar localizado en la bucofaringe, la cavidad bucal, la hipofaringe o la laringe. Los participantes no pueden presentar un tumor primario de la nasofaringe (de cualquier histología).
    2. Expresión tumoral de PD-L1 con una PPC ≥1.
    3. Al menos una lesión mensurable susceptible de inyección. La inyección IT para tratar lesiones cutáneas puede realizarse mediante inspección visual. La inyección IT para tratar lesiones subcutáneas puede realizarse guiada por ecografía o por palpación. Esta lesión inyectable debe ser mensurable y cumplir uno de los criterios siguientes:
    Lesión cutánea o subcutánea ≥1 cm de diámetro mayor en el caso de tumores sólidos o ≥1,5 cm de eje menor en el caso de lesión ganglionar en participantes con tumores sólidos. El diámetro mayor de una lesión inyectable debe ser ≤10 cm en el caso de tumores sólidos y lesiones ganglionares en pacientes con tumores sólidos.
    Múltiples lesiones superficiales coalescentes que, en conjunto, tienen ≥1 y ≤10 cm de diámetro mayor.
    4. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
    5. Función orgánica adecuada,
    6. Resultados del análisis del estado relativo al VPH en el cáncer bucofaríngeo, definido como un análisis IHQ de p16 con el ensayo de p16 CINtec® Histology y un punto de corte del 70 % (véanse los detalles en el manual de procedimientos). En caso de que se hayan realizado previamente análisis de VPH, no será necesario repetirlos.
    7. Varón o mujer de al menos 18 años de edad (sin límite superior) en el momento de firmar el consentimiento informado.
    8. Los varones participantes con capacidad para procrear deberán comprometerse a utilizar un método anticonceptivo muy eficaz durante las relaciones sexuales con mujeres en edad fértil desde la administración de la primera dosis de la medicación del estudio y hasta 120 días después de la última dosis del tratamiento del estudio.
    9. Las mujeres participantes en edad fértil deberán estar dispuestas a utilizar un método anticonceptivo muy eficaz, estar esterilizadas quirúrgicamente o abstenerse de mantener relaciones heterosexuales durante todo el estudio y hasta 120 días después de recibir la última dosis de la medicación del estudio. Se entiende por mujeres en edad fértil aquellas que no están esterilizadas quirúrgicamente o no llevan más de un año sin menstruación.
    10. Las mujeres en edad fértil deben tener un resultado negativo en una prueba de embarazo en orina o suero realizada en la selección y de nuevo en las 72 horas previas a la administración de la primera dosis del tratamiento del estudio. 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. El resultado de esta última deberá ser negativo para poder participar.
    11. Aceptar voluntariamente participar otorgando el consentimiento informado por escrito. El participante también podrá otorgar su consentimiento para las investigaciones biomédicas futuras. No obstante, podrá participar en el ensayo principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    12. Los participantes infectados por el VIH deberán cumplir estos criterios adicionales: a) Infección por el VIH-1 documentada mediante el uso de cualquier prueba del VIH rápida autorizada o kit de inmunoensayo enzimático o de quimioluminiscencia (E/CIA) para el VIH en cualquier momento antes de la entrada en el estudio (día 1). La infección por el VIH-1 se confirmará mediante una inmunotransferencia autorizada o un segundo análisis con anticuerpos mediante un método distinto de la prueba de VIH rápida o E/CIA inicial, mediante el antígeno p24 del VIH-1 o la carga viral plasmática de ARN del VIH-1.
    b) Tener bien controlado el VIH con tratamiento antirretroviral (TAR), definido como:
    1) Recuento de linfocitos T CD4+ >350 células/mm3 en el momento de la selección.
    2) Consecución y mantenimiento de la supresión virológica, definida como una concentración confirmada de ARN del VIH por debajo de 50 copias/ml o por debajo del límite inferior de cuantificación (LIC) según el análisis disponible localmente en el momento de la selección y durante al menos 12 semanas antes de la selección.
    3) Recepción de una pauta terapéutica estable (sin cambios en los fármacos ni modificación de las dosis) durante al menos 4 semanas antes de la incorporación al estudio (día 1).
    E.4Principal exclusion criteria
    1.Has disease that is suitable for local therapy administered with curative intent
    2. Has progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
    3. Has had chemotherapy or biological cancer therapy in the recurrent or metastatic setting for the treatment of HNSCC
    4. Has had radiation therapy within 2 weeks prior to randomization or subject has not fully recovered from adverse events due to a previously administered treatment
    5. Is expected to require any other form of antineoplastic therapy while on study
    6. Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for at least 2 years
    7. Has clinically active CNS metastases and/or carcinomatous
    meningitis. Participants with previously treated brain or meningeal metastases may participate and be eligible for treatment provided they are stable and asymptomatic, have no evidence of new or enlarging brain metastases, are evaluated within 4 weeks prior to first study intervention administration, and are off immunosuppressive doses of systemic steroids at least 2 weeks prior to enrolment
    8. Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, is not considered a form of systemic treatment and is allowed. Use of nonsystemic steroids is permitted
    9. 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 trial treatment. Corticosteroid use as premedication for allergic reactions is allowed
    10. Has had an allogenic tissue/solid organ transplant
    11. Has a history of vasculitis
    12. Has a history of interstitial lung disease
    13. Has an active infection requiring systemic therapy
    14. Has a known history of active tuberculosis
    15. Has a history of pneumonitis that required steroids or current pneumonitis
    16. Has had a severe hypersensitivity reaction to treatment a monoclonal antibody/component of the study intervention
    17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study in the opinion of the treating investigator
    18. Participants with known Hepatitis B or C infections or known to be positive for HBsAg/HBV DNA or Hepatitis C Antibody or RNA.
    19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or if the patient has previously participated in Merck MK-3475 clinical trials
    20. HIV infected participants who have had an HIV-related opportunistic infection within 6 months
    21. HIV infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
    22. Has known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the study
    23. Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
    24. Has not fully recovered from any effects of major surgery without significant detectable infection. Surgeries that required general anesthesia must be completed at least 2 weeks before first study intervention administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study intervention administration and participants should be recovered
    25. Has a tumor(s) in direct contact or encases a major blood vessel with or without ulceration and/or fungation onto the skin surface at the projected injection site in the head or neck.
    26. Has a history of reirradiation for HNSCC at the projected injection site in the head and neck
    27. Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted
    28. Drug-drug interactions have to be taken into consideration, and decisions whether a particular drug can be used as a concomitant medication in the study should be based on recommendations at the time of the study and depending on the MOA of the study drug. Patients on ART agents with a potentially significant overlapping toxicity profile should be excluded if the therapy cannot be switched to the regimen without overlapping toxicity.
    29. Has been treated with a STING agonist
    30. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or used an investigational device, any of which occurred within 4 weeks of the first dose of treatment.
    1.Presencia de enfermedad susceptible de tratamiento para su curación.
    2.Progresión de la enfermedad en los 6 meses siguientes al final de un tratamiento sistémico con intención curativa por CECC local o regionalmente avanzado.
    3.Recepción de quimioterapia o tratamiento biológico contra el cáncer en contexto recurrente o metastásico para el tratamiento del CECC.
    4.Radioterapia en las 2 semanas previas a la aleatorización o ausencia de recuperación plena del paciente de AEs debidos a un tratamiento administrado previamente.
    5.Previsión de que se precise otro tratamiento antineoplásico durante el estudio.
    6.Antecedentes de una segunda neoplasia maligna, a menos que se haya completado un tratamiento curativo sin signos de neoplasia maligna durante al menos 2 años.
    7.Presencia de metástasis activas en el SNC y/o meningitis carcinomatosa. Los participantes con metástasis cerebrales o meníngeas tratadas previamente podrán participar y ser elegibles para el tratamiento si se encuentran estables y asintomáticos, no presentan metástasis cerebrales nuevas o que hayan aumentado de tamaño, sean evaluados en las 4 semanas previas a la primera administración del tratamiento del estudio y no hayan recibido dosis inmunodepresoras de esteroides sistémicos durante al menos 2 semanas antes de la inclusión.
    8.Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico en los 2 últimos años, excepto vitíligo o atopia/asma infantil resuelta. El tratamiento de reposición, no se considera una forma de tratamiento sistémico y está permitido. El uso de esteroides no sistémicos está permitido.
    9.Diagnóstico de inmunodeficiencia o recepción de esteroides sistémicos algún otro tipo de tratamiento inmunodepresor en los 7 días previos a la primera dosis del tratamiento. Se permite el uso de corticoesteroides como premedicación para evitar reacciones alérgicas.
    10.Recepción de un alotrasplante de órgano sólido/tejidos.
    11.Antecedentes de vasculitis.
    12.Antecedentes de neumopatía intersticial.
    13.Infección activa con necesidad de tratamiento sistémico.
    14.Antecedentes conocidos de tuberculosis activa
    15.Antecedentes de neumonitis que haya precisado esteroides o presencia de una neumonitis activa.
    16. Reacción de hipersensibilidad grave al tratamiento con anticuerpo monoclonal o con componentes de la intervención del estudio.
    17.Antecedentes o signos de cualquier proceso, tratamiento o anomalía analítica que, según el investigador encargado del tratamiento, pueda confundir los resultados del estudio, dificultar la participación del paciente durante todo el estudio.
    18.Participantes con infecciones conocidas por el virus de la hepatitis B o C o con positividad conocida para HBsAg/ADN del VHB o anticuerpos o ARN del virus de la hepatitis C.
    19.Recepción de tratamiento anterior con un agente anti-PD-1, anti-PD-L1 o anti-PD-L2 o participación previa del paciente en estudios clínicos de Merck sobre MK-3475.
    20.Participantes infectados por el VIH que hayan tenido una infección oportunista relacionada con el VIH en los 6 meses anteriores.
    21.Infección por el VIH con antecedentes de sarcoma de Kaposi y/o enfermedad de Castleman multicéntrica.
    22.Presencia de un trastorno psiquiátrico o por abuso de sustancias.
    23.Embarazo, período de lactancia o intención de concebir o engendrar un hijo durante el período del estudio, desde la visita de selección hasta 120 días
    después de la última dosis del estudio.
    24.Ausencia de recuperación plena de una intervención de cirugía mayor sin infección significativa. Las intervenciones que precisen anestesia general deberán practicarse al menos 2 semanas antes de la primera administración del estudio. Las que precisen anestesia regional/epidural deberán practicarse al menos 72H antes de la 1ª administración del estudio y los participantes deberán haberse recuperado.
    25.Presencia de un tumor que está en contacto directo o encierre un vaso sanguíneo importante con/sin ulceración y/o micosis en superficie cutánea en el lugar de inyección previsto en cabeza o cuello.
    26.Antecedentes de irradiación repetida para el CECC en el lugar de inyección previsto en la cabeza y cuello.
    27.Recepción de vacuna de virus vivos en los 30 días previos al comienzo del tratamiento. Se permite el uso de vacunas contra la gripe sin virus vivos.
    28.Deben tenerse en cuenta las interacciones farmacológicas. Los pacientes que reciban TAR con un perfil de toxicidad solapado significativo serán excluidos del estudio si no es posible cambiar el tratamiento a la pauta sin toxicidad solapada.
    29.Recepción de tratamiento con agonista de STING
    30.Recepción de fármaco de un estudio, o participación en un estudio de un fármaco en investigación y recepción del tratamiento del estudio o uso de un dispositivo en investigación en las 4 semanas previas a la 1ª dosis del tratamiento. Se permite la participación en la fase de seguimiento (sin recibir tratamiento del estudio) de un estudio anterior
    E.5 End points
    E.5.1Primary end point(s)
    1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    1. Tasa de respuesta objetiva (TRO) según los criterios Criterios de Evaluación de Respuesta en tumores sólidos V1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 2 years
    1. Hasta aproximadamente 2 años
    E.5.2Secondary end point(s)
    1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    3. Overall Survival (OS)
    4. Number of participants experiencing an Adverse Event (AE)
    5. Number of participants discontinuing study treatment due to an Adverse Event (AE)
    1. supervivencia sin progresión (SSP) según los criterios Criterios de Evaluación de Respuesta en tumores sólidos V1.1
    2. duración de la respuesta (DR) según los criterios Criterios de Evaluación de Respuesta en tumores sólidos V1.1
    3. Supervivencia Global (SG)
    4. Número de participantes que tengan Acontecimientos adversos (AA)
    5. Número de participantes que discontinúen por algún Acontecimientos adverso (AA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 2 years
    2. Up to approximately 2 years
    3. Up to approximately 2 years
    4. Up to approximately 2 years
    5. Up to approximately 2 years
    1. Hasta aproximadamente 2 años
    2. Hasta aproximadamente 2 años
    3. Hasta aproximadamente 2 años
    4. Hasta aproximadamente 2 años
    5. Hasta aproximadamente 2 años
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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
    Australia
    Austria
    Brazil
    France
    Israel
    Korea, Republic of
    Mexico
    Norway
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years5
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 200
    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)
    None
    Ninguna
    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 Decision2020-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-28
    P. End of Trial
    P.End of Trial StatusOngoing
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