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    Summary
    EudraCT Number:2018-003808-39
    Sponsor's Protocol Code Number:MK-3475-866
    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:2019-04-12
    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 number2018-003808-39
    A.3Full title of the trial
    A Phase 3, Randomized Double Blind Study to Evaluate Peri-operative Pembrolizumab (MK-3475) + Neoadjuvant Chemotherapy versus Perioperative Placebo + Neoadjuvant Chemotherapy in Cisplatin-Eligible Participants with Muscle-invasive Bladder Cancer (KEYNOTE-866)
    Estudio de fase 3, aleatorizado y doble ciego para evaluar pembrolizumab (MK-3475) perioperatorio + quimioterapia neoadyuvante frente a un placebo perioperatorio + quimioterapia neoadyuvante en participantes con cáncer de vejiga con invasión muscular que son aptos para recibir cisplatino (KEYNOTE-866)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Trial of Perioperative Pembrolizumab + Neoadjuvant Chemotherapy vs. Perioperative Placebo + Neoadjuvant Chemotherapy for Cis-Eligible MIBC
    Ensayo de fase 3 de pembrolizumab perioperatorio + quimioterapia neoadyuvante frente a un placebo perioperatorio + quimioterapia neoadyuvante en el CVIM apto para cisplatino
    A.4.1Sponsor's protocol code numberMK-3475-866
    A.5.4Other Identifiers
    Name:INDNumber:122753
    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.5.3.4CountrySudan
    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 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.3.9.2Current 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 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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Muscle Invasive Bladder Cancer
    Cáncer de vejiga con invasión muscular
    E.1.1.1Medical condition in easily understood language
    Muscle Invasive Bladder Cancer
    Cáncer de vejiga con invasión muscular
    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 10005003
    E.1.2Term Bladder cancer
    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 pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab + neoadjuvant chemotherapy + Radical Cystectomy (RC) + Pelvic Lymph Node Dissection [PLND]) and Arm B (preoperative placebo + neoadjuvant chemotherapy + RC+ PLND), based on central pathology review, in participants whose tumors express programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥10 and in all participants, irrespective of CPS score.
    2. To compare event-free survival (EFS) between Arm A (perioperative pembrolizumab + neoadjuvant chemotherapy + RC + PLND) and Arm B (perioperative placebo + neoadjuvant chemotherapy + RC + PLND), evaluated in participants whose tumors express PD-L1 CPS ≥10 and in all participants, irrespective of CPS score.
    1.Comparar las tasas de respuesta completa anatomopatológica (RCap) obtenidas en el grupo A (pembrolizumab preoperatorio + quimioterapia neoadyuvante + cistectomía radical (CR) + disección de ganglios linfáticos pélvicos [DGLP]) y el grupo B (placebo preoperatorio + quimioterapia neoadyuvante + CR + DGLP), basándose en una revisión anatomopatológica centralizada, en participantes cuyos tumores expresen ligando 1 de muerte programada (PD-L1) con una puntuación positiva combinada (PPC) ≥ 10 y en todos los participantes, independientemente de la puntuación PPC.
    2.Comparar la supervivencia sin acontecimientos (SSA) entre el grupo A (pembrolizumab perioperatorio + quimioterapia neoadyuvante + CR + DGLP) y el grupo B (placebo perioperatorio + quimioterapia neoadyuvante + CR + DGLP), evaluados en los participantes cuyos tumores expresan PD-L1 con una PPC ≥ 10 y en todos los participantes, con independencia de la PPC.
    E.2.2Secondary objectives of the trial
    1. To compare the overall survival (OS) between Arm A and Arm B, evaluated in participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
    2. To assess disease-free survival (DFS) in participants from Arm A and Arm B, who are disease free after surgery based on participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
    3. To compare the rate of pathologic downstaging (pDS) between Arm A and Arm B, evaluated in participants whose tumors express PD-L1, CPS ≥10 and all participants, irrespective of CPS score.
    4. To evaluate the safety and tolerability of pembrolizumab + chemotherapy + RC + PLND.
    1-Comparar la supervivencia global (SG) entre el grupo A (pembrolizumab perioperatorio + quimioterapia neoadyuvante + CR + DGLP) y el grupo B (placebo perioperatorio + quimioterapia neoadyuvante + CR + DGLP), evaluados en los participantes cuyos tumores expresan PD-L1 con una PPC ≥ 10 y en todos los participantes, con independencia de la PPC.
    2.Evaluar la supervivencia sin enfermedad (SSE) entre los participantes del grupo A y del grupo B, que estén libres de enfermedad después de la cirugía, basándose en los participantes cuyos tumores expresan PD-L1 con una PPC ≥ 10 y en todos los participantes, con independencia de la PPC.
    3.Comparar la tasa de descenso del estadio anatomopatológico (DEap) entre el grupo A y el grupo B evaluados en los participantes cuyos tumores expresan PD-L1 con una PPC ≥ 10 y en todos los participantes, con independencia de la PPC.
    4.Evaluar la seguridad y la tolerabilidad de pembrolizumab + quimioterapia + CR + DGLP.
    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 and/or tissue and/or others 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 de uso futuro en ADN (sangre y/o tejido y/u otros especímenes recogidos durante este ensayo clínico). El objetivo de dichas investigaciones es el examiner biomarcadores para responder a preguntas emergentes que no están descritas en el protocolo (como parte del studio principal), y solo se llevarán a cabo en especímenes de aquellos pacientes que hayan consentido. El objetivo de la recogida de los especímenes para investigaciones de uso futuro es explorar e identificar biomarcadores que ayuden a in entendimiento científico de las enfermedades y/o de sus tratamientos terapéuticos. El objetivo principal es el uso de dicha información para el desarrollo de fármacos más seguros y efectivos, y/o asegurar que los pacientes reciben la dosis correcta del fármaco correcto en el momento adecuado.
    E.3Principal inclusion criteria
    To be eligible for inclusion in this study, the participant must:
    1. Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR):
    - Participants with mixed histology are eligible provided the urothelial component is ≥50% as noted above.
    - Participants whose tumors contain any neuroendocrine component are not eligible.
    - Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible.
    2. Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR.
    3. Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
    4. Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to enrollment [ICF signed]) that is submitted and adequate to determine histology, muscle invasion, and PD-L1 status by central pathology vendor. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification.
    5. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
    6. Have demonstrated adequate organ function (all screening labs should be performed within 14 days prior to randomization).
    7. Participant is male or female and at least 18 years of age inclusive, at the time of signing the informed consent.
    8. A male participant must agree to use contraception as detailed in Appendix 5 of this protocol during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus an additional 90 days [a spermatogenesis cycle] for study treatments where there is risk of clinically relevant genotoxicity) after the last dose of study treatment and refrain from donating sperm during this period.
    9. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least 1 of the following conditions applies:
    a. Not a woman of childbearing potential (WOCBP)
    b. WOCBP who agrees to follow the contraceptive guidance:Contraceptive Guidance and Pregnancy Testing during the treatment period and for at least 180 days (corresponding to time needed to eliminate any study treatment(s) [pembrolizumab and or any active combination] plus 30 days [a menstruation cycle] for study treatments with risk of genotoxicity) after the last dose of study treatment.
    10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. 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.
    1. Tener un diagnóstico confirmado histológicamente de cáncer de vejiga con invasión muscular (T2-T4aN0M0), con histología urotelial predominante (≥ 50 %) (la histología y la presencia de invasión muscular se confirmarán mediante RCIE):
     Los participantes con histología mixta podrán ser incluidos siempre que el componente urotelial sea ≥ 50 %, como se ha señalado anteriormente.
     No son aptos los participantes cuyos tumores contengan cualquier componente neuroendocrino.
     Los carcinomas uroteliales que no tengan su origen en la vejiga (por ejemplo, vías altas [uréteres, pelvis renal], uretra) no son elegibles.
    2. Tener un cáncer de vejiga sin metástasis clínicas (N0M0) determinado mediante estudios de imagen (TC de tórax y TC o RM de abdomen/pelvis), confirmado mediante RCIE.
    3. Ser considerado apto para CR + DGLP por su urólogo y/o oncólogo y aceptar someterse a una CR + DGLP estándar con intención curativa (incluida prostatectomía si procede) de acuerdo con las directrices AUA/ASTRO/ASCO/SUO referenciadas en el Apéndice 9 de la sección 10.9.
    4. Disponer de una muestra de resección transuretral (RTU) de un tumor vesical (en los 60 días previos a la inclusión [firma del DCI]) adecuada para la determinación de la histología, la invasión muscular y el estado de PD-L1 por el laboratorio central de anatomía patológica. En caso de que la muestra no permita evaluar el PD-L1, se asignará al participante al grupo de PPC < 10 con fines de estratificación. 5. Tener un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
    6. Presentar una función orgánica adecuada según se define en la Tabla 5 (todos los análisis de selección deberán practicarse en los 14 días previos a la aleatorización).
    7. Participantes de ambos sexos que tengan al menos 18 años en el momento de la firma del consentimiento informado.
    8. Los varones participantes deberán comprometerse a utilizar métodos anticonceptivos, detallados en el apéndice 5 de este protocolo, durante el período de tratamiento y durante al menos 180 días (el tiempo necesario para eliminar los tratamientos del estudio [pembrolizumab y/o cualquier combinación activa] más otros 90 días [un ciclo de espermatogénesis] en el caso de los tratamientos del estudio con los que exista riesgo de genotoxicidad clínicamente importante) después de la última dosis del tratamiento del estudio, además de abstenerse de donar semen durante este período.
    9. Podrán participar en el estudio las mujeres que no estén embarazadas (apéndice 5), no estén dando el pecho y cumplan al menos una de las condiciones siguientes:
    a. No es una mujer en edad fértil (MEF), según la definición del apéndice 5.
    b. Es una MEF y acepta seguir las normas sobre anticonceptivos recogidas en el apéndice 5: Normas sobre anticoncepción y pruebas de embarazo, durante el período de tratamiento y durante al menos 180 días (el tiempo necesario para eliminar los tratamientos del estudio [pembrolizumab y/o cualquier combinación activa] más otros 30 días [un ciclo menstrual] en el caso de los tratamientos del estudio con riesgo de genotoxicidad) después de la última dosis del tratamiento del estudio.
    10. El participante (o su representante legal cuando proceda) otorga su consentimiento/asentimiento informado por escrito para el estudio. El participante también podrá otorgar su consentimiento/asentimiento para las investigaciones biomédicas futuras. No obstante, podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    E.4Principal exclusion criteria
    1. Has a known additional malignancy that is progressing or has required active anti-cancer treatment ≤3years of study randomization
    2. Has received any prior systemic anti-neoplastic treatment for MIBC.
    3. Has an abdomino-pelvic lymph node ≥15 mm in the short axis.
    4. Is cisplatin-ineligible, as defined by meeting any one of the following criteria:
    - Impaired renal function with measured or calculated creatinine clearance (CrCl) <60 mL/min (calculated by Cockcroft-Gault method or 24-hour urine collection).
    - ECOG Performance Status ≥ 2
    - CTCAE v.4 Grade ≥2 audiometric hearing loss (threshold shift of >25 dB averaged at 2 consecutive test frequencies in at least 1 ear; testing is not required at screening; it may be performed at investigator’s discretion)
    - CTCAE v.4 Grade ≥2 peripheral neuropathy
    - New York Heart Association (NYHA) Class III heart failure
    5. 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).
    6. Has received therapy with hematopoietic growth factor such as granulocyte-colony stimulating factor (G-CSF) or GM-CSF in 14 days prior to randomization.
    7. Has received prior systemic anti-cancer therapy including investigational agents within 3 years of randomization.
    8. Has received any prior radiotherapy to the bladder.
    9. 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, BCG, 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.
    10. Is currently participating in or has participated in a study of an investigational agent orhas used an investigational device within 4 weeks prior to the first dose of study intervention.
    11. 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 the first dose of study drug.
    12. Has hypersensitivity to mAbs (including pembrolizumab) and/or any of their excipients.
    13. Has severe hypersensitivity (≥Grade 3) to cisplatin and/or gemcitabine and any of their excipients.
    14. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
    15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
    16. Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection.
    17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection. Note: No testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
    19. 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.
    20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
    21. 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 intervention.
    22. Has had an allogenic tissue/solid organ transplant.
    1. Tiene otra neoplasia maligna conocida que está en progresión o ha necesitado tratamiento antineoplásico activo en los 3 años previos a la aleatorización del estudio. Nota: No se excluirá a los participantes con carcinoma basocelular o espinocelular de la piel o con carcinoma in situ (por ejemplo, carcinoma de mama o cáncer de cuello uterino in situ) que se hayan sometido a un tratamiento potencialmente curativo. No se excluirá a los participantes con cáncer de vejiga sin invasión muscular (CVSIM) previo que estén recibiendo tratamiento antes de la aleatorización. No se excluirá a los participantes con cáncer de próstata de bajo riesgo (T1-T2a, puntuación de Gleason ≤ 6 y antígeno prostático específico [PSA] ≤ 10 ng/ml) tratados con intención definitiva en cualquier momento antes de la selección o no tratados y sometidos a vigilancia activa.
    2. Ha recibido cualquier tratamiento antineoplásico sistémico previo contra el CVIM.
    3. Tiene un ganglio linfático abdominopélvico ≥ 15 mm en el eje menor.
    4. No es apto para recibir cisplatino, lo que se define como el cumplimiento de uno cualquiera de los siguientes criterios:
     Insuficiencia renal con aclaramiento de creatinina (CrCl) medido o calculado < 60 ml/min (calculado por el método de Cockcroft-Gault o con la orina de 24 horas).
     Estado funcional del ECOG ≥ 2.
     Hipoacusia audiométrica de grado ≥ 2 según los CTCAE v.4 (desplazamiento del umbral >25 dB promediado en dos frecuencias consecutivas en al menos un oído; no es obligatorio realizar la prueba en la selección; podrá realizarse a criterio del investigador).
     Neuropatía periférica de grado ≥ 2 según los CTCAE v.4.
     Insuficiencia cardíaca en clase III de la New York Heart Association (NYHA).
    5. Ha recibido 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).
    6. Ha recibido tratamiento con factor de crecimiento hematopoyético, como factor estimulador de las colonias de granulocitos (G-CSF) o GM-CSF en los 14 días previos a la aleatorización.
    7. Ha recibido tratamiento antineoplásico sistémico previo, incluidos fármacos en investigación, los tres años anteriores a la aleatorización.
    8. Ha recibido radioterapia previa en la vejiga.
    9. Ha recibido una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del fármaco del estudio. Son ejemplos de vacunas de microorganismos vivos, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela/zóster, contra la fiebre amarilla, antirrábica, 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 (por ejemplo, FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
    10. Está participando actualmente o ha participado en un estudio de un fármaco en investigación o ha usado un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis de la intervención del estudio.
    11. Tiene un diagnóstico de inmunodeficiencia o está recibiendo 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 a la primera dosis del fármaco del estudio.
    12. Tiene hipersensibilidad a los AcM (incluido pembrolizumab) y/o a cualquiera de sus excipientes.
    13. Presenta hipersensibilidad grave (grado ≥ 3) a cisplatino y/o gemcitabina y a cualquiera de sus excipientes.
    14. Tiene una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticosteroides o inmunodepresores) en los dos últimos años. El tratamiento de reposición (por ejemplo, tiroxina, insulina o corticosteroides en dosis fisiológicas por insuficiencia suprarrenal o hipofisaria) no se considera una forma de tratamiento sistémico y se permite su uso.
    15. Tiene antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroides o presenta una neumonitis activa.
    16. Tiene una infección activa con necesidad de tratamiento sistémico. El participante podrá repetir el proceso de selección una vez resuelta la infección.
    17. Tiene 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 (véase el apéndice 7).
    18. Tiene antecedentes de hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o infección activa por el virus de la hepatitis C (definida como un valor detectable de ARN del VHC mediante análisis cualitativo de ácidos nucleicos). Nota No es necesario realizar pruebas de hepatitis B y C a menos lo exijan autoridades sanitarias .RESTO leer Protoc
    E.5 End points
    E.5.1Primary end point(s)
    1. Pathologic Complete Response Rate in All Participants
    2. Pathologic Complete Response Rate in Participants Whose Tumors Express PD-L1, CPS ≥10
    3. Event-Free Survival in All Participants
    4. Event-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
    1-Ratio de respuesta patológica completa en todos los participantes
    2-Ratio de respuesta patológica completa en los participantes cuyos tumores expresen PD-L1 con una PPC ≥10
    3-Supervivencia libre de eventos en todos los participantes
    4-Supervivencia libre de eventos en participantes cuyos tumores expresen PD-L1 con una PPC ≥10
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 4 months (Time of surgery)
    2. Up to approximately 4 months (Time of surgery)
    3. Up to approximately 5.5 years
    4. Up to approximately 5.5 years
    1- Aproximadamente hasta 4 meses ( momento de la cirugía)
    2-Aproximadamente hasta 4 meses (momento de la cirugía)
    3- Aproximadamente hasta 5,5 años
    3- Aproximadamente hasta 5,5 años
    E.5.2Secondary end point(s)
    1. Overall Survival in All Participants
    2. Overall Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
    3. Disease-Free Survival in All Participants
    4. Disease-Free Survival in Participants Whose Tumors Express PD-L1, CPS ≥10
    5. Pathologic Downstaging Rate in All Participants
    6. Pathologic Downstaging Rate in Participants Whose Tumors Express PD- L1, CPS ≥10
    7. Percentage of Participants Experiencing Adverse Events (AEs)
    8. Percentage of Participants Discontinuing Study Drug Due to an AE
    9. Percentage of Participants Experiencing Perioperative Complications
    10. Change in Patient-Reported Outcomes from Baseline in the Total Score of Functional Assessment of Cancer Therapy – General (FACT-G)
    11. Change in Patient-Reported Outcomes from Baseline in the Total Score FACT B1-Cys
    12. Change in Patient-Reported Outcomes from Baseline in FACT-B1-Cys-Trial Outcome Index (TOI)
    13. Change in Patient-Reported Outcomes from Baseline in EQ-5D-5L Visual Analog Score (VAS)
    14. Change in Patient-Reported Outcomes from Baseline in EQ-5D-5L Utility Score
    15. Time to Deterioration (TTD) in FACT-G
    16. Time to Deterioration in EQ-5D-5L VAS
    1-Supervivencia global en todos los participantes
    2-Supervivencia global en participantes cuyos tumores expresen PD-L1con una PPC ≥10
    3-Supervivencia libre de enfermedad en todos los participantes
    4-Supervivencia libre de enfermedad en participantes cuyos tumores expresen PD-L1 con una PPC ≥10
    5-Tasa de descenso del estadío anatomopatológico en todos los participantes
    6-Tasa de descenso del estadío anatomopatológico en participantes cuyos tumores expresen PD-L1 con una PPC ≥10
    7-Porcentaje de participantes que experimenten acontencimientos adversos (AA)
    8-Porcentaje de participantes que discontinuen el uso del fármaco a consencuencia de in acontecimiento adverso (AA)
    9-Porcentaje departicipantes que experimenten complicaciones perioperatorias
    10-Cambio en los acontencimientos reportados por los pacientes desde el momento basal en la puntuación total de la evaluación sobre la terapia contra el cáncer - General (FACT-G)
    11-Cambio en los acontencimientos reportados por los pacientes desde el momento basal en la puntuación total FACT B1-Cys
    12- Cambio en los acontencimientos reportados por los pacientes desde el momento basal en FACT-B1-Cys- índice del resultado del estudio (TOI)
    13-Cambio en los acontencimientos reportados por los pacientes desde el momento basal en la puntuación visual analógica (VAS) en EQ-5D-5L
    14-Cambio en los acontencimientos reportados por los pacientes desde el momento basal en la puntuación de utilidad de EQ-5D-5L
    15. Tiempo hasta el deterioro
    16-Tiempo hasta el deterioro de acuerdo a los criterios del EQ-5D-5L VAS
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 5.5 years
    2. Up to approximately 5.5 years
    3. From approximately 5 months up to approximately5.5 years
    4. From approximately 5 months up to approximately5.5 years
    5. Up to approximately 4 months (Time of surgery)
    6. Up to approximately 4 months (Time of surgery)
    7. Up to approximately 5.5 years
    8. Up to approximately 1 year
    9. Up to approximately 1 year
    10. Up to approximately 5.5 years
    11. Up to approximately 5.5 years
    12. Up to approximately 5.5 years
    13. Up to approximately 5.5 years
    14. Up to approximately 5.5 years
    15. Up to approximately 5.5 years
    16. Up to approximately 5.5 years
    1- Aproximadamente hasta 5,5 años
    2- Aproximadamente hasta 5,5 años
    3- Desde Aproximadamente 5 meses hasta aproximadamente 5,5 años
    4- Desde Aproximadamente 5 meses hasta aproximadamente 5,5 años
    5-Hasta aproximadamente 4 años( momento de la cirugía)
    6-Hasta aproximadamente 4 años( momento de la cirugía)
    7- Aproximadamente hasta 5,5 años
    8-Aproximadamente hasta 1 año
    9- Aproximadamente hasta 1 año
    10-Aproximadamente hasta 5,5 años
    11.Aproximadamente hasta 5,5 años
    12-Aproximadamente hasta 5,5 años
    13-Aproximadamente hasta 5,5 años
    14.Aproximadamente hasta 5,5 años
    15.Aproximadamente hasta 5,5 años
    16-Aproximadamente hasta 5,5 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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA76
    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
    Belgium
    Canada
    Denmark
    France
    Germany
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Sweden
    Thailand
    Turkey
    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
    LPLV
    LPLV
    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 months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months5
    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: 237
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 553
    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 state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 352
    F.4.2.2In the whole clinical trial 790
    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 Decision2019-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-17
    P. End of Trial
    P.End of Trial StatusOngoing
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