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    Summary
    EudraCT Number:2018-004116-22
    Sponsor's Protocol Code Number:MK-3475-921
    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:2019-03-27
    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 number2018-004116-22
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone versus Placebo Plus Docetaxel Plus Prednisone in Participants with Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) who have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)
    Estudio de fase 3, aleatorizado y doble ciego de pembrolizumab (MK-3475) más docetaxel más prednisona frente a un placebo más docetaxel más prednisona en participantes con cáncer de próstata resistente a la castración metastásico (CPRCm) sin quimioterapia previa que han mostrado progresión con un fármaco hormonal de última generación (FHUG) (KEYNOTE-921).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 Study of Pembrolizumab plus Docetaxel plus Prednisone in mCRPC
    Estudio de fase 3 de pembrolizumab más docetaxel en el CPRCm
    A.3.2Name or abbreviated title of the trial where available
    Phase 3 Study of Pembrolizumab plus Docetaxel in mCRPC
    Estudio de fase 3 de pembrolizumab más docetaxel en el CPRCm
    A.4.1Sponsor's protocol code numberMK-3475-921
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme de España S.A.
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressCalle Josefa Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913210805
    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
    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
    Metastatic Castration-Resistant Prostate Cancer
    cáncer de prostata metastásico resistente a la castración
    E.1.1.1Medical condition in easily understood language
    Metastatic Castration-Resistant Prostate Cancer
    cáncer de prostata metastásico resistente a la castración
    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 10076506
    E.1.2Term Castration-resistant prostate 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 pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone with respect to overall survival (OS)
    2. To compare pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone with respect to radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR)
    1.Comparar pembrolizumab más docetaxel más prednisona con placebo más docetaxel más prednisona en lo que respecta a la supervivencia global (SG).
    2.Comparar pembrolizumab más docetaxel más prednisona con placebo más docetaxel más prednisona en lo que respecta a la supervivencia sin progresión radiológica (SSPr) conforme a los Criterios de evaluación de la respuesta en tumores sólidos, versión 1.1 (RECIST 1.1) modificados por el Grupo de trabajo sobre el cáncer de próstata (PCWG), evaluada mediante una revisión central independiente y enmascarada (RCIE).
    E.2.2Secondary objectives of the trial
    1.Compare pembrolizumab plus docetaxel plus prednisone to placebo plus docetaxel plus prednisone with respect to time to initiation of the first subsequent anti-cancer therapy or death
    2.Evaluate pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to:PSA response rate;and ORR and DOR per PCWG-modified RECIST 1.1 as assessed by BICR
    3.Compare pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to:TTPP based on BPI-SF item 3 “worst pain in 24 hours” and opiate analgesic use;time to first SSRE;and time to PSA progression
    4.Compare pembrolizumab plus docetaxel plus prednisone versus placebo plus docetaxel plus prednisone with respect to the time to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1,as assessed by BICR
    1.Comparar pembrolizumab más docetaxel más prednisona con placebo más docetaxel más prednisona en lo que respecta al tiempo transcurrido hasta el inicio del primer tratamiento antineoplásico posterior o la muerte
    2.Evaluar pembrolizumab más docetaxel más prednisona en comparación con placebo más docetaxel más prednisona en lo que respecta:Tasa de respuesta por PSA o TRO y DR, conforme a criterios RECIST 1.1 modificados por PCWG, evaluadas RCIE.
    3.Comparar pembrolizumab más docetaxel más prednisona con placebo más docetaxel más prednisona en lo que respecta a: THPD basado en el apartado 3 “peor dolor en 24 horas” del cuestionario BPI-SF, Tiempo primer EOS,Tiempo progresión PSA
    4.Comparar pembrolizumab más docetaxel más prednisona con placebo más docetaxel más prednisona en lo que respecta al tiempo transcurrido hasta la progresión radiológica en las partes blandas conforme a las normas sobre partes blandas de criterios RECIST 1.1 modificados por el PCWG, evaluado mediante RCIE
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Exploratory Biomarker Research, Genetic (DNA) analysis from tumor, Tumor and blood RNA analyses, Proteomics and immunohistochemistry (IHC) using blood or tumor, Other biomarkers, Future Biomedical Research
    Investigación exploratoria de biomarcadores, análisis genético (ADN) de tumores, análisis de ARN tumoral y sanguíneo, proteómica e inmunohistoquímica (IHC) usando sangre o tumor, otros biomarcadores, investigación biomédica futura.
    E.3Principal inclusion criteria
    1. Have histologically- or cytologically-confirmed (if acceptable according to local health authority regulations) adenocarcinoma of the prostate without small cell histology. Diagnosis must be stated in a pathology report and confirmed by the investigator
    2. Have prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to screening, as determined by the investigator, by means of one of the following:
    a. PSA progression using local laboratory values as defined by a minimum of 2 consecutive rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥1 ng/mL
    b. Radiographic disease progression in soft tissue based on RECIST 1.1 criteria with or without PSA progression
    c. Radiographic disease progression in bone based on PCWG, defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression
    3. Have progression under the following conditions if the participant received antiandrogen therapy prior to enrollment:
    a. Evidence of progression >4 weeks since last flutamide treatment
    b. Evidence of progression >6 weeks since last bicalutamide or nilutamide treatment
    4. Have current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by CT/MRI. Participants whose disease spread is limited to regional pelvic lymph nodes are not eligible
    5. Have received prior treatment with either abiraterone acetate or enzalutamide (but not both) in the pre-chemotherapy mCRPC state and either
    a) progressed through treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression)
    OR
    b) have become intolerant of the drug (minimum 4 weeks treatment)
    6. Have ongoing androgen deprivation with serum testosterone <50 ng/mL (<2.0 nM). If the participant is currently being treated with luteinizing hormone-releasing hormone agonists or antagonists (participants who have not undergone an orchiectomy) this therapy must have been initiated at least 4 weeks prior to randomization and treatment must be continued throughout the study
    7. Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to randomization
    8. Demonstrate adequate organ function; all screening labs should be performed in the central laboratory within 10 days of the first dose of study intervention
    9. Participant is male
    10. Participant is ≥18 years of age on day of signing informed consent
    11. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days after the last dose of study invention:
    a) Refrain from donating sperm
    PLUS either:
    b) Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
    OR
    a) Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause as detailed below:
    Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
    12. Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex
    13. 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 adenocarcinoma de próstata confirmado por métodos histológicos o citológicos (siempre que sea aceptable conforme a las normas de las autoridades sanitarias locales), sin histología microcítica. El diagnóstico debe estar consignado en un informe anatomopatológico y ser confirmado por el investigador.
    2. Haber mostrado progresión del cáncer de próstata durante el tratamiento de privación androgénica (o después de una orquiectomía bilateral) en los 6 meses previos a la selección, según lo determinado por el investigador, definida por una de las circunstancias siguientes:
    a. Progresión por PSA según los valores del laboratorio local, definida como un mínimo de dos concentraciones crecientes consecutivas de PSA con un intervalo de al menos una semana entre cada determinación y con un valor de PSA en la fase de selección ≥ 1 ng/ml.
    b. Mostrar progresión radiológica de la enfermedad en las partes blandas conforme a los criterios RECIST 1.1, con o sin progresión por PSA.
    c. Mostrar progresión radiológica de la enfermedad en el hueso, según los criterios del PCWG, definida como la aparición de dos o más lesiones óseas nuevas en la gammagrafía ósea, con o sin progresión por PSA.
    3. Mostrar progresión en las circunstancias siguientes si el participante ha recibido tratamiento antiandrogénico antes de su reclutamiento:
    a. Signos de progresión más de 4 semanas después del último tratamiento con flutamida.
    b. Signos de progresión más de 6 semanas después del último tratamiento con bicalutamida o nilutamida.
    4. Presentar signos actuales de enfermedad metastásica, documentada por la existencia de lesiones óseas en la gammagrafía ósea o de afectación de partes blandas en la TC/RM. No podrán participar aquellos posibles participantes cuya diseminación de la enfermedad se encuentre limitada a los ganglios linfáticos pélvicos regionales.
    5. Haber recibido tratamiento previo con acetato de abiraterona o enzalutamida (pero no con ambos) en el contexto del CPRCm previo a la quimioterapia y a) haber mostrado progresión durante el mismo tras un mínimo de 8 semanas de tratamiento (mínimo de 14 semanas en los pacientes con progresión ósea). O BIEN b) haber mostrado intolerancia al fármaco (mínimo de 4 semanas de tratamiento).
    6. Estar en situación de privación androgénica persistente con una concentración sérica de testosterona < 50 ng/ml (< 2,0 nM). Si el participante está recibiendo agonistas o antagonistas de la gonadoliberina (participantes que no se hayan sometido a una orquiectomía), este tratamiento deberá haberse empezado al menos 4 semanas antes de la aleatorización y el tratamiento deberá mantenerse durante todo el estudio.
    7. Los participantes que se encuentren en tratamiento antirresortivo óseo (con bisfosfonatos o denosumab, entre otros) deberán haber recibido dosis estables durante al menos cuatro semanas antes de la aleatorización.
    8. Presentar una función orgánica adecuada, según se define en la Tabla 1; todos los análisis de selección deberán realizarse en el laboratorio central en los 10 días previos a la primera dosis de la intervención del estudio.
    9. El participante es varón.
    10. El participante tiene 18 años o más de edad el día de firma del consentimiento informado.
    11. Podrán participar en el estudio los varones que se comprometan a todo lo siguiente durante el período de intervención y hasta, como mínimo, 120 días después de recibir la última dosis de la intervención del estudio:
    a) Abstenerse de donar semen.
    MÁS:
    b) Abstenerse de mantener relaciones heterosexuales como modo de vida habitual y preferido (abstinencia a largo plazo y persistente) y compromiso de mantenerla.
    O
    a) Utilizar métodos anticonceptivos a menos que se confirme que presentan azoospermia (por vasectomía o secundaria a una causa médica tal como se detalla a continuación:
    - Comprometerse a utilizar preservativo masculino más uso por parte de la pareja de un método anticonceptivo adicional cuando mantengan relaciones sexuales con penetración vaginal con mujeres en edad fértil que no estén embarazadas.
    12. Los varones participantes deberán comprometerse a utilizar preservativo masculino en cualquier actividad que permita el paso de eyaculado a otra persona de cualquier sexo.
    13. 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, se 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 treatment in the last 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ that have undergone potentially curative therapy are not excluded
    2. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment
    3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
    4. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant, in the opinion of the treating investigator
    5. Has undergone major surgery including local prostate intervention ( excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications
    6. Has a gastrointestinal disorder affecting absorption
    7. Is unable to swallow tablets/capsules
    8. Has an active infection (including tuberculosis) requiring systemic therapy
    9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
    10. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
    11. Has known active human immunodeficiency virus, hepatitis B virus or hepatitis C virus. Testing at screening is not required unless mandated by local regulations
    12. Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
    13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
    14. Has CTCAE Grade ≥2 peripheral neuropathy, except when due to trauma
    15. Has ascites and/or clinically significant pleural effusion
    16. Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
    17. Has received a whole blood transfusion in the last 120 days prior to entry into the study. Packed red blood cells and platelet transfusions are acceptable if not given within 28 days of the first dose of study intervention
    18. Has received colony-stimulating factors within 28 days prior to the first dose of study intervention
    19. Has had a prior anticancer mAb within 4 weeks prior to randomization or who has not recovered from AEs due to mAbs administered more than 4 weeks prior to randomization
    20. Has used herbal products that may have hormonal anti prostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to treatment randomization
    21. Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
    22. 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
    23. Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
    24. Has had prior treatment with apalutamide or darolutamide
    25. Has hypersensitivity to docetaxel or polysorbate 80
    26. Participant is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
    27. Has had prior treatment with abiraterone acetate and progressed in the hormone-sensitive setting
    28. Has received prior targeted small molecule therapy or abiraterone acetate or enzalutamide within 4 weeks prior to the first dose of study intervention, or has not recovered from AEs due to a previously administered agent
    1. Presencia de otra neoplasia maligna conocida que está en progresión o ha precisado tratamiento activo en los últimos tres años. No se excluirá a los participantes con carcinoma basocelular o espinocelular de piel o carcinoma in situ que se hayan sometido a un tratamiento potencialmente curativo.
    2. Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico en los dos últimos años. El tratamiento de reposición no se considera una forma de tratamiento sistémico.
    3. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis de la intervención del estudio.
    4. 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.
    5. Práctica de una intervención de cirugía mayor, incluida una intervención prostática local (excepto biopsia de próstata), en los 28 días previos a la aleatorización sin recuperación adecuada de la toxicidad y/o complicaciones.
    6. Presencia de un trastorno digestivo que afecte a la absorción.
    7. Incapacidad de tragar comprimidos o cápsulas.
    8. Presencia de una infección activa (incluida la tuberculosis) con necesidad de tratamiento sistémico.
    9. Antecedentes de neumonitis (no infecciosa) que haya precisado la administración de esteroides o presencia de una neumonitis activa.
    10. Presencia de un trastorno psiquiátrico o por abuso de sustancias que pueda dificultar el cumplimiento de los requisitos del ensayo.
    11. Presencia de infección activa conocida por el virus de la inmunodeficiencia humana (VIH), el virus de la hepatitis B o el virus de la hepatitis C . No será necesario realizar análisis en la fase de selección a menos que lo exija la normativa local.
    12. Presencia de metástasis activas conocidas en el sistema nervioso central o meningitis carcinomatosa. Los posibles participantes con metástasis cerebrales tratadas con anterioridad podrán participar siempre que se encuentren estables, no presenten indicios de metástasis cerebrales nuevas o que estén aumentando de tamaño y no utilicen esteroides durante al menos 7 días antes de recibir el tratamiento del ensayo. Esta excepción no se aplica a la meningitis carcinomatosa, que será motivo de exclusión con independencia de la estabilidad clínica.
    13. Presencia de hipersensibilidad grave (grado ≥ 3) a pembrolizumab y/o a cualquiera de sus excipientes.
    14. Presencia de neuropatía periférica de grado ≥ 2 según los criterios CTCAE, excepto cuando se deba a un traumatismo.
    15. Presencia de ascitis y/o derrame pleural clínicamente significativo.
    16. Presencia de insuficiencia cardíaca congestiva sintomática (cardiopatía en clase III o IV según la New York Heart Association).
    17. Recepción de una transfusión de sangre completa en los 120 días previos a su incorporación al estudio. Los concentrados de eritrocitos y las transfusiones de plaquetas se consideran aceptables si no se han administrado en los 28 días previos a la primera dosis de la intervención del estudio.
    18. Recepción de factores estimulantes de colonias en los 28 días previos a la primera dosis de la intervención del estudio.
    19. Recepción de un anticuerpo monoclonal antineoplásico en las 4 semanas previas a la aleatorización o ausencia de recuperación de acontecimientos adversos provocados por anticuerpos monoclonales administrados más de 4 semanas antes de la aleatorización.
    20. Utilización de productos de herbolario que podrían tener actividad hormonal contra el cáncer de próstata y/o que se sabe que disminuyen las concentraciones de PSA en las 4 semanas previas a la aleatorización al tratamiento.
    21. Recepción de tratamiento previo con radio u otros radiofármacos terapéuticos contra el cáncer de próstata.
    22. Recepción de 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
    23. Recepción de tratamiento previo con docetaxel u otra quimioterapia contra el CPRCm.
    24. Tratamiento previo con apalutamida o darolutamida
    25. Hipersensibilidad a docetaxel o al polisorbato 80.
    26. Recepción activa de inhibidores potentes o moderados de la enzima 3A4 del citocromo P450 (CYP3A4) que no pueden suspenderse durante el estudio.
    27. Tratamiento previo con acetato de abiraterona y progresión en el contexto hormonosensible
    28. Recepción de tratamiento dirigido con moléculas pequeñas, acetato de abiraterona o enzalutamida en las 4 semanas previas a la primera dosis de la intervención del estudio o ausencia de recuperación de los acontecimientos adversos provocados por un fármaco administrado anteriormente.
    E.5 End points
    E.5.1Primary end point(s)
    1. Overall Survival (OS)
    2. Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    1.Supervivencia Global
    2. Supervivencia sin progresión radiológica (SSPr) conforme a los criterios RECIST 1.1 modificados por el PCWG
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 28 months
    2. Up to approximately 28 months
    1.Hasta aproximadamente 28 meses
    2.Hasta aproximadamente 28 meses
    E.5.2Secondary end point(s)
    1. Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST)
    2. Prostate-specific Antigen (PSA) Response Rate
    3. Objective Response Rate (ORR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    4. Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    5. Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 (“Worst Pain in 24 Hours”) and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score)
    6. Time to First Symptomatic Skeletal-related Event (SSRE)
    7. Time to Prostate-specific Antigen (PSA) Progression
    8. Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    9. Number of Participants Who Experience an Adverse Event (AE)
    10. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
    1. Tiempo transcurrido hasta el inicio del primer tratamiento antineoplásico posterior o la muerte (TPTP)
    2. Tasa de respuesta por PSA
    3. Tasa de respuestas objetivas conforme a los criterios RECIST 1.1 modificados por el PCWG
    4. Duración de la respuesta (DR) conforme a los criterios RECIST 1.1 modificados por el PCWG, evaluado mediante una RCIE
    5. Tiempo transcurrido hasta la progresión del dolor (THPD) basado en el apartado 3 “peor dolor en 24 horas” del cuestionario BPI-SF
    6. Tiempo transcurrido hasta el primer episodio óseo sintomático (EOS)
    7. Tiempo transcurrido hasta la progresión del PSA
    8.Tiempo transcurrido hasta la progresión radiológica en las partes blandas conforme a las normas sobre partes blandas de los criterios RECIST 1.1 modificados por el PCWG
    9. Número de participantes que experimentan efectos adversos (EA)
    10. Número de participantes que suspenden el tratamiento por efectos adversos (EA)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 28 months
    2. Up to approximately 28 months
    3. Up to approximately 28 months
    4. Up to approximately 28 months
    5. Up to approximately 28 months
    6. Up to approximately 28 months
    7. Up to approximately 28 months
    8. Up to approximately 28 months
    9. Up to approximately 28 months
    10. Up to approximately 28 months
    1. Hasta aproximadamente 28 meses
    2. Hasta aproximadamente 28 meses
    3. Hasta aproximadamente 28 meses
    4. Hasta aproximadamente 28 meses
    5. Hasta aproximadamente 28 meses
    6. Hasta aproximadamente 28 meses
    7. Hasta aproximadamente 28 meses
    8. Hasta aproximadamente 28 meses
    9. Hasta aproximadamente 28 meses
    10. Hasta aproximadamente 28 meses
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 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 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 concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA86
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Brazil
    Canada
    Chile
    Colombia
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Russian Federation
    Spain
    Taiwan
    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 years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 750
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 494
    F.4.2.2In the whole clinical trial 1000
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguna
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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