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    Summary
    EudraCT Number:2018-002601-57
    Sponsor's Protocol Code Number:MK-3475-913
    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:2018-11-05
    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 number2018-002601-57
    A.3Full title of the trial
    A Phase 3 Open-label, Single Arm Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) as First-line Therapy in Participants With Advanced Merkel Cell Carcinoma (KEYNOTE-913))
    Estudio de fase 3, abierto y de un solo grupo para evaluar la seguridad y la eficacia de pembrolizumab (MK-3475) como tratamiento de primera línea en participantes con carcinoma de células de Merkel avanzado (KEYNOTE-913)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab (MK-3475) as First-Line Therapy for Advanced Merkel Cell Carcinoma
    Pembrolizumab (MK-3475) como tratamiento de primera línea del carcinoma de células de Merkel avanzado
    A.3.2Name or abbreviated title of the trial where available
    Pembrolizumab (MK-3475) as First-Line Therapy for Advanced Merkel Cell Carcinoma
    Pembrolizumab (MK-3475) como tratamiento de primera línea del carcinoma de células Merkel avanzado
    A.4.1Sponsor's protocol code numberMK-3475-913
    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 AddressC/ Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid, España
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34943210590
    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.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
    Unresectable Stage III and Stage IV Merkel Cell Carcinoma (MCC)
    Merkel Cell Carcinoma (MCC) estadio III y IV irresecable.
    E.1.1.1Medical condition in easily understood language
    Advanced Merkel Cell Carcinoma (MCC)
    carcinoma de células Merkel avanzado(CCM)
    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 LLT
    E.1.2Classification code 10064025
    E.1.2Term Merkel cell carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the objective response rate (ORR), as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following administration of pembrolizumab)
    Evaluar la tasa de respuestas objetivas (TRO), según una revisión centralizada independiente y enmascarada (RCIE) conforme a los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST 1.1), modificados para seguir un máximo de 10 lesiones diana y de 5 lesiones diana por órgano, tras la administración de pembrolizumab.
    E.2.2Secondary objectives of the trial
    1) To assess duration of response (DOR), as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following administration of pembrolizumab
    2) To assess the progression-free survival (PFS), as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following administration of pembrolizumab
    3) To assess overall survival (OS) following administration of pembrolizumab
    4) To assess safety and tolerability of treatment with pembrolizumab
    1)Evaluar la duración de la respuesta (DR), según una RCIE conforme a los criterios RECIST 1.1, modificados para seguir un máximo de 10 lesiones diana y de 5 lesiones diana por órgano, tras la administración de pembrolizumab.
    2)Evaluar la supervivencia sin progresión (SSP), según una RCIE conforme a los criterios RECIST 1.1, modificados para seguir un máximo de 10 lesiones diana y de 5 lesiones diana por órgano, tras la administración de pembrolizumab.
    3)Evaluar la supervivencia global (SG) tras la administración de pembrolizumab.
    4)Evaluar la seguridad y la tolerabilidad del tratamiento con pembrolizumab.
    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 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
    Merck llevará a cabo investigaciones biomédicas futuras con las muestras de ADN (sangre) obtenidas durante este estudio clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores con el fin de abordar cuestiones nuevas 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 investigaciones biomédicas futuras consiste en estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y/o sus tratamientos. El objetivo último es utilizar tal información para desarrollar fármacos más seguros y eficaces y/o para garantizar que los sujetos reciban la dosis correcta del fármaco adecuado en el momento preciso.
    E.3Principal inclusion criteria
    1. Have histologically confirmed diagnosis of locoregional MCC that has recurred following standard locoregional therapy with surgery and/or radiation therapy and is not amenable to local therapy or metastatic MCC (Stage IV) as per American Joint Committee on Cancer (AJCC) 8th edition guidelines
    2. Have been untreated for advanced or metastatic disease except as follows:
    a. Prior intratumoral therapy will be permitted
    b. Prior adjuvant or neoadjuvant therapy containing systemic chemotherapy will be permitted if treatment concluded at least 3 months prior to C1D1
    c. Prior adjuvant or neoadjuvant therapy containing anti-PD-1/L1 or anti-CTLA-4 therapy will not be permitted
    3. Have at least 1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria as determined by the local site investigator/radiology assessment. Measurable disease will be verified by BICR prior to treatment allocation. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
    4. Toxic effect(s) of the most recent prior therapy have resolved to Grade 1 or less (except alopecia). If participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention
    5. Be male or female and at least 12 years of age, at the time of signing the informed consent/assent
    6. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    7. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of childbearing potential (WOCBP)
    OR
    - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days (corresponding to the time needed to eliminate any study intervention) after the last dose of study intervention
    - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours before the first dose of study intervention
    - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
    8. Participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study and agrees to OS data collection until the study endpoints are reached. The participant may also provide consent/assent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research
    9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 or Lansky Play-Performance Scale (LPS) ≥50 for pediatric participants up to and including 16 years of age
    10. Have adequate organ function
    1. Tener un diagnóstico confirmado histológicamente de CCM locorregional que haya recidivado después del tratamiento locorregional convencional con cirugía y/o radioterapia y no sea susceptible de tratamiento local o CCM metastásico (estadio IV) según las directrices del American Joint Committee on Cancer (AJCC), 8ª edición.
    2. No haber recibido tratamiento contra la enfermedad avanzada o metastásica, con las excepciones siguientes.
    a. Se permitirá el tratamiento intratumoral previo.
    b. Se permitirá el tratamiento adyuvante o neoadyuvante previo con quimioterapia sistémica siempre que el tratamiento haya concluido al menos tres meses antes del día 1 del ciclo 1.
    c. No se permitirá el tratamiento adyuvante o neoadyuvante previo con un fármaco anti-PD-1/L1 o anti-CTLA-4.
    3. Presentar al menos una lesión mensurable mediante tomografía computarizada (TC) o resonancia magnética (RM) conforme a los criterios RECIST 1.1 según lo determinado por el investigador del centro o la evaluación radiológica local. La enfermedad mensurable se verificará mediante una RCIE antes de la asignación del tratamiento. Las lesiones ubicadas en una zona previamente irradiada se considerarán mensurables siempre que se haya constatado progresión en dichas lesiones. Nota: Las lesiones cutáneas y otras lesiones superficiales no se consideran lesiones mensurables a efectos de este protocolo, pero pueden considerarse lesiones no diana.
    4. Presentar resolución de los efectos tóxicos del tratamiento previo más reciente hasta un grado 1 o inferior (excepto la alopecia). Cuando el participante se haya sometido a cirugía mayor o haya recibido > 30 Gy de radioterapia, tendrá que haberse recuperado de la toxicidad y/o las complicaciones de la intervención.
    5. Ser varón o mujer y tener 12 años o más de edad en el momento de firmar el consentimiento/asentimiento informado.
    6. El uso de anticonceptivos por los varones deberá cumplir la normativa local sobre métodos anticonceptivos para los participantes en estudios clínicos.
    7. El uso de anticonceptivos por las mujeres deberá cumplir la normativa local sobre métodos anticonceptivos para los participantes en estudios clínicos.
    • Una mujer podrá participar si no está embarazada, no está amamantando y cumple al menos una de las condiciones siguientes:
    - No es una mujer en edad fértil (MEF).
    - O
    - Es una MEF y utiliza un método anticonceptivo muy eficaz (con un índice de fallos < 1 % anual), con baja dependencia de la usuaria, o practica la abstinencia de relaciones heterosexuales como modo de vida preferido y habitual (abstinencia a largo plazo y persistente), según se describe en el apéndice 5, durante el período de intervención y hasta al menos 120 días (correspondiente al tiempo necesario para eliminar cualquier intervención del estudio) después de la última dosis de la intervención del estudio. El investigador deberá evaluar la posibilidad de fracaso del método anticonceptivo (es decir, incumplimiento, inicio reciente) en relación con la primera dosis de la intervención del estudio.
    - Las MEF deberán dar negativo en una prueba de embarazo de alta sensibilidad (en orina o suero, según exija la normativa local) en las 72 horas previas a la primera dosis de la intervención del estudio.
    - Cuando el resultado de una prueba en orina no pueda confirmarse que es negativo (por ejemplo, resultado ambiguo), 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.
    8. El participante (o su representante legal, si procede) otorga su consentimiento/asentimiento informado por escrito para el estudio y acepta la recogida de datos sobre SG hasta que se alcancen los criterios de valoración del estudio. El participante también podrá otorgar su consentimiento/asentimiento para investigaciones biomédicas futuras. No obstante, podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    9. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1 o una puntuación en la escala LPS (Escala de rendimiento en el juego de Lansky) ≥ 50 en los participantes pediátricos de hasta 16 años, inclusive (apéndice 9).
    10. Presencia de una función orgánica adecuada,
    E.4Principal exclusion criteria
    1. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
    2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
    3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to C1D1
    4. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
    5. Has an active autoimmune disease that has required systemic treatment in past 2 years
    6. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    7. Has an active infection requiring systemic therapy
    8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
    10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
    11. Has clinically significant cardiac disease within 6 months of C1D1, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
    12. 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
    13. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    14. Has not received standard locoregional therapy with surgery and/or radiation therapy for the treatment of local or locoregional disease
    15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
    16. Has received prior systemic anticancer therapy including investigational agents within 12 weeks prior to C1D1
    17. Has received radiotherapy within 2 weeks prior to start of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids
    18. Has received a live vaccine within 30 days prior to C1D1
    19. 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 C1D1
    20. Is pregnant or 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
    21. Has had an allogenic tissue/solid organ transplant
    1. Presencia de otra neoplasia maligna conocida que está en progresión o que ha necesitado tratamiento activo en los últimos dos años.
    Nota: No se excluirá a los participantes con carcinoma basocelular o espinocelular de piel, melanoma primario no ulcerado < 1 mm de profundidad sin afectación ganglionar o carcinoma in situ (por ejemplo, carcinoma de mama o cáncer de cuello uterino in situ) que se hayan sometido a un tratamiento potencialmente curativo.
    2. Presencia de metástasis activas en el SNC o de meningitis carcinomatosa. Los participantes con metástasis cerebrales tratadas anteriormente podrán participar siempre que se encuentren radiológicamente estables, es decir, sin signos de progresión durante al menos cuatro semanas en estudios de imagen repetidos (hay que señalar que durante la selección para el estudio deberán realizarse nuevos estudios de imagen), clínicamente estables y sin necesidad de tratamiento con esteroides durante al menos 14 días antes de la primera dosis de la intervención del estudio.
    3. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico 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 al día 1 del ciclo 1.
    4. Presencia de hipersensibilidad grave (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus excipientes.
    5. 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.
    6. Antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroides o presencia de una neumonitis activa.
    7. Infección activa con necesidad de tratamiento sistémico
    8. 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.
    9. Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección activa por el virus de la hepatitis C (definida como detección de ARN del virus de la hepatitis C [VHC] [cualitativo]).
    10. Antecedentes de tuberculosis activa (Bacillus tuberculosis).
    11. Presencia de una cardiopatía clínicamente significativa en los seis meses previos al día 1 del ciclo 1, como insuficiencia cardíaca congestiva en clase III o IV de la New York Heart Association, angina inestable, infarto de miocardio, accidente cerebrovascular o arritmia cardíaca asociada a inestabilidad hemodinámica
    12. 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 posible participante.
    13. Presencia de un trastorno psiquiátrico o por abuso de sustancias que podría dificultar la capacidad del participante para colaborar en el cumplimiento de los requisitos del estudio.
    14. No recepción de tratamiento locorregional convencional con cirugía y/o radioterapia para tratar la enfermedad local o locorregional. Nota: Este criterio de exclusión no es aplicable a los participantes diagnosticados de CCM irresecable o metastásico.
    15. Recepción de un 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 estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    16. Recepción de un tratamiento antineoplásico sistémico previo, incluidos fármacos en investigación, en las 12 semanas previas al día 1 del ciclo 1.
    17. Recepción de radioterapia en las dos semanas previas al comienzo de la intervención del estudio. Los participantes deberán haberse recuperado de toda la toxicidad relacionada con la radioterapia y no precisar corticoides.
    18. Recepción de una vacuna de microorganismos vivos en los 30 días previos al día 1 del ciclo 1. Algunos ejemplos de vacunas de microorganismos vivos son, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela, contra la fiebre amarilla, antirrábica, bacilo de Calmette-Guérin (BCG) y antitifoidea. Las vacunas inyectables contra la gripe estacional contienen, por lo general, virus muertos y están permitidas; en cambio, las vacunas antigripales intranasales (p. ej., FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
    19. Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro READ the rest in PROTOCOL
    E.5 End points
    E.5.1Primary end point(s)
    Objective Response (RO), definded as complete response ro partial response.
    Respuesta objetiva (RO): respuesta completa (RC) o parcial (RP).
    E.5.1.1Timepoint(s) of evaluation of this end point
    approx. 2 years
    aproximadamente 2 años
    E.5.2Secondary end point(s)
    1) Duration of Response (DOR): The time from first response (Complete Response or Partial Response) to subsequent disease progression, or death from any cause, whichever occurs first.
    2) Progression-free Survival (PFS): The time from the first day of study treatment to the first confirmed disease progression or death due to any cause, whichever occurs first
    3) Overall Survival (OS): The time from the first day of study treatment to death due to any cause
    4) Adverse events (AEs)
    5) Study intervention discontinuation due to AEs
    1)DR: tiempo transcurrido entre la primera respuesta (RC o RP) y la progresión posterior de la enfermedad o la muerte por cualquier causa, lo que antes ocurra.
    2)SSP: tiempo transcurrido entre el primer día de tratamiento del estudio y la primera progresión documentada de la enfermedad o la muerte por cualquier causa, lo que antes ocurra.
    3)SG: tiempo transcurrido entre el primer día de tratamiento del estudio y la muerte por cualquier causa.
    4)Acontecimientos adversos (AA)
    5)Suspensión de la intervención del estudio por AA.
    E.5.2.1Timepoint(s) of evaluation of this end point
    approx. 13 years
    Aproximadamente 13 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 Yes
    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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    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 EEA16
    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
    Canada
    France
    Italy
    New Zealand
    Spain
    Sweden
    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 years13
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years13
    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 Yes
    F.1.1Number of subjects for this age range: 1
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 1
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 9
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 41
    F.4.2.2In the whole clinical trial 50
    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
    Ninguno
    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 Decision2019-02-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-23
    P. End of Trial
    P.End of Trial StatusOngoing
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