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    Summary
    EudraCT Number:2018-003809-26
    Sponsor's Protocol Code Number:MK-3475-905
    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 number2018-003809-26
    A.3Full title of the trial
    A Phase 3 Randomized Study of Cystectomy plus Perioperative Pembrolizumab versus Cystectomy Alone in Cisplatin-ineligible Participants with Muscleinvasive Bladder Cancer (KEYNOTE-905)
    Estudio de fase 3 aleatorizado de cistectomía más pembrolizumab perioperatorio frente a cistectomía sola en participantes con cáncer de vejiga con invasión muscular no aptos para recibir cisplatino (KEYNOTE-905)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 trial of perioperative pembrolizumab for cisplatin-ineligible patients with MIBC
    Ensayo de fase 3 de pembrolizumab perioperatorio en pacientes con cáncer de vejiga con invasión muscular (CVIM) no aptos para recibir cisplatino
    A.3.2Name or abbreviated title of the trial where available
    A Phase 3 trial of perioperative pembrolizumab for cisplatin-ineligible patients with MIBC
    Ensayo de fase 3 de pembrolizumab perioperatorio en pacientes con CVIM con invasión muscular.
    A.4.1Sponsor's protocol code numberMK-3475-905
    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 Corp., a subsidiary of Merck & Co., Inc.
    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
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210600
    B.5.5Fax number+34913210590
    B.5.6E-mailensayos_clinicos@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePEMBROLIZUMAB
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name 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.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
    Muscle-invasive Bladder Cancer (MIBC)
    Cáncer de vejiga con invasión muscular (CVIM)
    E.1.1.1Medical condition in easily understood language
    Participants with muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based chemotherapy
    Participantes con carcinoma urotelial con invasión muscular que no son candidatos a la quimioterapia basada en cisplatino.
    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 10022877
    E.1.2Term Invasive bladder cancer
    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
    1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab [MK-3475] and radical cystectomy [RC] + pelvic lymph node dissection [PLND]) and Arm B (RC+PLND), based on central pathologic review, evaluated in participants whose tumors express programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10 and all participants, irrespective of CPS score.
    2. To compare event-free survival (EFS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS score.
    1.Comparar las tasas de respuesta completa anatomopatológica (RCap) obtenidas en los grupos A (pembrolizumab preoperatorio y CR + LP) y B (CR + LP), basándose en una revisión anatomopatológica centralizada, evaluadas en participantes cuyos tumores expresan una PPC de PD-L1 ≥ 10 y en todos los participantes, con independencia de la puntuación PPC.
    2. Comparar la supervivencia sin acontecimientos (SSA) entre los grupos A (pembrolizumab perioperatorio y CR+LP y B (CR+LP), evaluada en los participantes cuyos tumores expresan una PPC de PD-L1 ≥ 10 y en todos los participantes, con independencia de la puntuación PPC.
    E.2.2Secondary objectives of the trial
    1. To compare overall survival (OS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in individuals 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 (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND) 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 rates of pathologic downstaging (pDS) between Arm A (preoperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), 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 perioperative pembrolizumab with RC+PLND.
    1.Comparar la supervivencia global (SG) entre los grupos A (pembrolizumab perioperatorio y CR+LP) y B (CR+LP), evaluada en participantes cuyos tumores expresan una PPC de PD-L1 ≥ 10 y en todos los participantes, con independencia de la puntuación PPC.
    2. Evaluar la supervivencia sin enfermedad (SSE) en participantes del grupo A (pembrolizumab perioperatorio y CR+LP) y el grupo B (CR+LP) que no presenten enfermedad después de la intervención quirúrgica, basándose en los participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10 y en todos los participantes, con independencia de la puntuación PPC.
    3. Comparar las tasas de descenso del estadio anatomopatológica TNM (DEap) entre el grupo A (pembrolizumab preoperatorio y CR + LP) y el grupo B (CR + LP), evaluados en participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10 y en todos los participantes, con independencia de la puntuación PPC.
    4. Evaluar la seguridad y la tolerabilidad de pembrolizumab perioperatorio con CR+LP.
    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
    Meck llevará a cabo investigaciones biomédicas futuras (sangre) con las muestras obtenidas de forma sistemática y específica durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores para abordar aspectos nuevos que no se describen en otras partes del rotocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los sujetos que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigación biomédica futura consiste en estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal información para desarrollar vacunas y fármacos más seguros y eficaces o para garantizar que los sujetos reciban la dosis correcta del fármaco o la vacuna adecuados en el momento preciso
    E.3Principal inclusion criteria
    -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%
    *Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible
    *Participants whose tumors contain any neuroendocrine component are not eligible
    -Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR
    -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
    -Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
    *Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
    *ECOG Performance Status 2
    *CTCAE v.4 Grade ≥2 audiometric hearing loss (25 dB in two consecutive wave ranges))
    *CTCAE v.4 Grade ≥2 peripheral neuropathy
    *NYHA Class III heart failure
    -Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to study enrollment [ICF signed]) which is submitted and adequate for evaluation of histology, muscle invasion and PD-L1 status. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification.
    Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
    -Must have an ECOG performance status of 0, 1, or 2
    -Demonstrate adequate organ function (all screening labs should be performed within 14 days prior to randomization)
    -Participant is male or female at least 18 years of age, at the time of signing the informed consent
    -A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
    -A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
    *Not a woman of childbearing potential (WOCBP) or
    *A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after study interventions
    -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
    -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 participar siempre que el componente urotelial sea ≥ 50 %, como se ha señalado anteriormente.
    *No podrán participar los carcinomas uroteliales que no se originen en la vejiga (por ejemplo, vías altas [uréteres, pelvis renal], uretra).
    * No podrán participar los participantes cuyos tumores contengan cualquier componente neuroendocrino.
    -Tener un cáncer de vejiga sin metástasis clínica (N0M0) determinado mediante estudios de imagen (TC de tórax y TC o RM de abdomen/pelvis), confirmado mediante RCIE.
    - Ser considerado apto para la CR + LP por su urólogo y/u oncólogo y aceptar someterse a RC + LP estándar con intención curativa (incluida prostatectomía, si procede) de acuerdo con las directrices AUA/ASTRO/ASCO/SUO.
    - No ser aptos para el tratamiento con cisplatino, lo que se define por el hecho de cumplir al menos uno de los siguientes criterios:
    * Insuficiencia renal con CrCl medido o calculado de 30 a 59 ml/min (calculado con el método de Cockcroft-Gault o medido en orina de 24 horas).
    *Estado funcional del ECOG 2
    * Hipoacusia audiométrica de grado ≥ 2 según los criterios CTCAE, versión 4 (25 dB en dos rangos de onda consecutivos).
    *Neuropatía periférica de grado ≥2 según los CTCAE v.4
    *Insuficiencia cardíaca de clase III de la NYHA
    - Someterse a una resección transuretral (RTU) de un tumor vesical (obtenida en los 60 días previos a la inclusión en el estudio [firma del DCI]) que se presente y sea adecuada para evaluar la histología, invasión muscular y estado relativo a PD-L1. En caso de que la muestra no sea evaluable para PD-L1, se asignará al participante al grupo PPC <10 para la estratificación.
    Se prefiere el uso de bloques de tejido fijados en formol e incluidos en parafina (FFIP) a los cortes para microscopio.
    - Tiene un estado funcional del ECOG de 0, 1 o 2.
    - Presentar una función orgánica suficiente (todos los análisis de selección deberán practicarse en los 14 días previos a la aleatorización)
    - El participante es un varón o una mujer de 18 años o más de edad en el momento de firmar el consentimiento informado.
    - Los varones deben comprometerse a utilizar métodos anticonceptivos durante el período de tratamiento y hasta, como mínimo, 120 días después de la última dosis del tratamiento del estudio, así como a abstenerse de donar semen durante este período.
    - Una mujer podrá participar en el estudio 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 que se compromete a seguir las normas relativas a métodos anticonceptivos indicadas en el apéndice 5 durante el período de tratamiento y hasta, como mínimo, 120 días después de la última intervención del estudio.
    - 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
    -Has a known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization
    -Has received any prior systemic anti-neoplastic treatment for MIBC
    -Has an abdomino-pelvic lymph node ≥15 mm in the short axis
    -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)
    -Has received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization
    -Has received any prior radiotherapy to the bladder
    -Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (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
    -Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
    -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
    -Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
    -Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
    -Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
    -Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection
    -Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    -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
    -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
    -Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    -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
    -Has had an allogenic tissue/solid organ transplant
    - Presentar una neoplasia maligna no urotelial adicional conocida que está en progresión o ha precisado tratamiento activo en ≤3 años a la aleatorización en el estudio.
    - Ha recibido cualquier tratamiento antineoplásico sistémico previo contra el CVIM.
    - Tener un ganglio linfático abdominopélvico ≥ 15 mm en el eje menor.
    - 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).
    - Ha recibido tratamiento antineoplásico sistémico previo, incluidos fármacos en investigación, en los tres años previos a la aleatorización.
    - Ha recibido radioterapia previa en la vejiga
    - Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del fármaco del estudio. Algunos ejemplos de vacunas de microorganismos vivos son, entre otros, los siguientes: vacuna contra el sarampión, antiparotídica, antirrubeólica, contra la varicela/zoster (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 (por ejemplo, FluMist®) son vacunas de virus vivos atenuados y no están permitidas.
    - Participación activa o pasada en un estudio de un fármaco en investigación o uso de un dispositivo en investigación en las cuatro semanas previas a la administración de la primera dosis de la intervención del estudio.
    - 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 a la primera dosis del fármaco del estudio.
    - Tiene hipersensibilidad a los anticuerpos monoclonales (incluido pembrolizumab) y/o a cualquiera de sus excipientes.
    - Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, uso de 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
    - Antecedentes de neumonitis (no infecciosa) que haya precisado la administración de esteroides o presencia de una neumonitis activa.
    - Infección activa con necesidad de tratamiento sistémico. El participante podrá someterse de nuevo al proceso de selección una vez resuelta la infección
    - Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH). No será necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
    - Antecedentes de infección por el virus de la hepatitis B (definido como 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] mediante análisis cualitativo del ácido nucleico).
    - 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.
    - 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.
    - Embarazo, período de lactancia o intención de concebir o engendrar un hijo durante el período previsto del estudio, desde la visita de selección hasta 120 días después de la última dosis de la intervención del estudio.
    - Recepción de un alotrasplante de órgano sólido o tejidos.
    E.5 End points
    E.5.1Primary end point(s)
    1. Pathological Complete Response (pCR) Rate in All Participants
    2. pCR Rate in Participants Whose Tumors Express Programmed Cell Death Ligand 1 (PD-L1) at a Combined Positive Score (CPS) ≥10
    3. Event-Free Survival (EFS) in All Participants
    4. EFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
    1. Tasa de respuesta completa anatomopatológica (RCap) en todos los participantes
    2. Tasa de respuesta completa anatomopatológica en participantes cuyos tumores expresen una puntuación positiva combinada (PPC) del ligando tipo 1 del receptor de muerte celular programada (PD-L1) ≥10
    3. supervivencia sin acontecimientos (SSA) en todos los participantes
    4. SSA en los participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 3 months (Time of surgery)
    2. Up to approximately 3 months (Time of surgery)
    3. Up to approximately 5.5 years
    4. Up to approximately 5.5 years
    1. Hasta 3 meses aproximadamente (momento de la cirugía)
    2. Hasta 3 meses aproximadamente (momento de la cirugía)
    3. Hasta 5.5 años aproximadamente
    4. Hasta 5.5 años aproximadamente
    E.5.2Secondary end point(s)
    1. Overall Survival (OS) in All Participants
    2. OS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
    3. Disease-Free Survival (DFS) in All Participants
    4. DFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
    5. Pathologic Downstaging (pDS) Rate in All Participants
    6. pDS Rate in Participants Whose Tumors Express PD-L1 at a CPS ≥10
    7. Percentage of Participants Experiencing an Adverse Event (AE)
    8. Percentage of Participants Discontinuing Study Treatment due to an AE
    9. Percentage of Participants Experiencing Perioperative Complications
    1. Supervivencia global (SG) en todos los participantes
    2. SG en los participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10.
    3. Supervivencia sin enfermedad (SSE) en todos los participantes
    4. SSE en los participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10.
    5. Tasas de descenso del estadio anatomopatológico TNM (DEap) en todos los participantes
    6. DEap en los participantes cuyos tumores expresen una PPC de PD-L1 ≥ 10.
    7. Porcentaje de participantes que experimentanV un acontecimiento adverso (AA)
    8. Porcentaje de participantes que suspendan el tratamiento del estudio por un AA
    9. Porcentaje de participantes que presenten complicaciones preoperatorias
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 6.5 years
    2. Up to approximately 6.5 years
    3. Up to approximately 5.5 years
    4. Up to approximately 5.5 years
    5. Up to approximately 3 months (Time of surgery)
    6. Up to approximately 3 months (Time of surgery)
    7. Up to approximately 6.5 years
    8. Up to approximately 1 year
    9. Up to approximately 1 year
    1. Hasta 6.5 años aproximadamente
    2. Hasta 6.5 años aproximadamente
    3. Hasta 5.5 años aproximadamente
    4. Hasta 5.5 años aproximadamente
    5. Hasta 3 meses aproximadamente (momento de la cirugía)
    6. Hasta 3 meses aproximadamente (momento de la cirugía)
    7 Hasta 6.5 años aproximadamente
    8. Hasta 1 año aproximadamente
    9. Hasta 1 año aproximadamente
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Cistectomía
    Cystectomy
    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 EEA105
    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
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months10
    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: 305
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 305
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 408
    F.4.2.2In the whole clinical trial 610
    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)
    The subjects will be treated per standard of care post participation in the study.
    Los sujetos serán tratados según el estándar de atención posterior a la participación en el estudio.
    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 Decision2019-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-24
    P. End of Trial
    P.End of Trial StatusOngoing
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