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    Summary
    EudraCT Number:2016-000589-47
    Sponsor's Protocol Code Number:MK-3475-427
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-05
    Trial results View 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 number2016-000589-47
    A.3Full title of the trial
    A Phase II Single-arm, Open-label Monotherapy Clinical Trial of Pembrolizumab (MK-3475) in Locally Advanced/Metastatic Renal Cell Carcinoma (mRCC) (KEYNOTE-427)
    Ensayo clínico de fase II, abierto y de un solo grupo para evaluar el uso de pembrolizumab (MK-3475) en monoterapia en el carcinoma renal metastásico (CRm) o localmente avanzado (KEYNOTE-427)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab in advanced renal cell carcinoma
    Pembrolizumab en el carcinoma renal avanzado
    A.3.2Name or abbreviated title of the trial where available
    Pembrolizumab in advanced renal cell carcinoma
    Pembrolizumab en el carcinoma renal avanzado
    A.4.1Sponsor's protocol code numberMK-3475-427
    A.5.4Other Identifiers
    Name:KEYNOTENumber:427
    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
    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 Yes
    D.2.1.1.1Trade name Keytruda
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp and Dohme, Ltd
    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.3.1Product namepembrolizumab
    D.3.2Product code MK-3475; SCH900475
    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.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    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
    Renal cell carcinoma (clear cell & non-clear cell), or kidney cancer
    Carcinoma de células renales (células claras y células no claras), o cáncer de riñón
    E.1.1.1Medical condition in easily understood language
    Renal cell carcinoma (clear cell & non-clear cell), or kidney cancer
    Carcinoma de células renales (células claras y células no claras), o cáncer de riñón
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10023400
    E.1.2Term Kidney cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To estimate the objective response rate (ORR) per RECIST 1.1 as assessed by BICR in subjects with clear cell RCC.
    2. To estimate the ORR per RECIST 1.1 as assessed by BICR in subjects with non-clear cell RCC.
    1. Determinar la tasa de respuestas objetivas (TRO) conforme a los criterios RECIST 1.1, evaluada mediante una RCIE, en sujetos con CR de células claras.
    2. Determinar la TRO conforme a los criterios RECIST 1.1, evaluada mediante una RCIE, en sujetos con CR de células no claras.
    E.2.2Secondary objectives of the trial
    1. To estimate the duration of response (DOR), disease control rate (DCR), and the progression-free survival (PFS) per RECIST 1.1 as assessed by BICR and overall survival (OS) in subjects with clear cell or non-clear cell RCC by cohort.
    2. To determine the safety and tolerability of pembrolizumab in subjects with clear cell or non-clear cell RCC by cohort.
    3. To describe the patient population using the International Metastatic RCC Database Consortium (IMDC) risk group : favorable versus intermediate versus poor risk groups in subjects with clear cell or non-clear cell RCC by cohort [1,2,3].
    1. Calcular la duración de la respuesta (DR), tasa de control de la enfermedad (TCE) y supervivencia sin progresión de la enfermedad (SSP) conforme a los criterios RECIST 1.1, evaluadas mediante una RCIE, y la supervivencia global (SG) en sujetos con CR de células claras o células no claras según la cohorte.
    2. Determinar la seguridad y tolerabilidad de pembrolizumab en sujetos con CR de células claras o células no claras según la cohorte.
    3. Describir la población de pacientes según el grupo de riesgo del IMDC (International Metastatic RCC Database Consortium) (consulte en el apéndice 12.5 los criterios del IMDC): riesgo favorable frente a intermedio frente a desfavorable, en sujetos con CR de células claras o células no claras según la cohorte [1,2,3].
    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 tissue) 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.
    El promotor realizará investigaciones biomédicas futuras con las
    muestras obtenidas para tal finalidad durante este ensayo clínico. Dichas
    investigaciones podrán incluir análisis genéticos (ADN), determinación
    de perfiles de expresión génica (ARN), proteómica, metabolómica
    (suero, plasma) y/o determinación de otros analitos.
    Estas investigaciones tendrán por objeto el análisis de biomarcadores
    con el fin de abordar aspectos nuevos que no se describen en otras
    partes del protocolo (como parte del ensayo principal) y solo se llevarán
    a cabo en muestras de los sujetos que hayan otorgado el consentimiento
    correspondiente. El objetivo de la obtención de muestras para
    investigaciones biomédicas futuras consiste en estudiar e identificar
    biomarcadores que proporcionen información a los científicos sobre las
    enfermedades y/o sus tratamientos. El objetivo último consiste en
    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 vacuna adecuado en el momento preciso.
    E.3Principal inclusion criteria
    - Provide written informed consent/assent for the trial
    - Be > or = 18 years of age on day of signing informed consent
    - Cohort A (clear cell cohort) must have histologically confirmed diagnosis of clear cell RCC or RCC with clear cell component (with or without sarcomatoid features)
    - Cohort B (non-clear cell cohort) must have histologically confirmed diagnosis of non-clear cell RCC (with or without sarcomatoid features). Confirmation of the diagnosis of non-clear cell RCC by central histology review during the screening phase is required prior to allocation to Cohort B
    - Have locally advanced/metastatic disease, i.e., Stage IV RCC per American Joint Committee on Cancer (AJCC) or have recurrent disease
    - Have measurable disease per RECIST 1.1 as assessed by BICR. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
    - Have received no prior systemic therapy for advanced RCC
    - Provide adequate tissue for biomarker analysis for cohorts A and B
    - Demonstrate adequate organ function
    - Otorgar su consentimiento o asentimiento informado para el estudio.
    - Tener una edad mínima de 18 años el día de firma del consentimiento informado.
    - La cohorte A (cohorte con CR de células claras) deberá tener un diagnóstico confirmado histológicamente de CR de células claras o CR con componente de células claras (con o sin características sarcomatoideas).
    - La cohorte B (cohorte con CR de células no claras) deberá tener un diagnóstico confirmado histológicamente de CR de células no claras (con o sin características sarcomatoideas). Antes de la asignación a la cohorte B se exigirá confirmación del diagnóstico de CR de células no claras mediante un examen histológico centralizado durante la fase de selección
    - Presentar enfermedad localmente avanzada/metastásica, es decir, CR en estadio IV según el American Joint Committee on Cancer (AJCC), o enfermedad recurrente.
    - Presentar enfermedad mensurable conforme a los criterios RECIST 1.1, evaluada mediante una RCIE. Las lesiones diana ubicadas en una zona previamente irradiada se considerarán mensurables siempre que se haya constatado progresión en dichas lesiones.
    - No haber recibido ningún tratamiento sistémico previo para el CR avanzado.
    - Proporcionar tejido suficiente para un análisis de biomarcadores en las cohortes A y B
    - Presentar una función orgánica adecuada
    E.4Principal exclusion criteria
    - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to allocation, has had major surgery within 4 weeks prior to allocation or radiation therapy within 2 weeks prior to allocation, or who has not recovered (i.e., < or = Grade 1 or at baseline) from adverse events due to prior treatment
    - Had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR
    - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment, except in the case of central nervous system (CNS) metastases
    - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents
    - Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ are not excluded
    - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
    - Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
    - Has had a prior solid organ transplant
    - Está participando o ha participado en un estudio de un fármaco o dispositivo en investigación en las cuatro semanas previas a la asignación del tratamiento o se ha sometido a una intervención de cirugía mayor en las cuatro semanas previas a la asignación del tratamiento o a radioterapia en las dos semanas previas a la asignación del tratamiento o bien no se ha recuperado (es decir, recuperación a un grado ≤ 1 o la situación basal) de los AA debidos al tratamiento previo.
    - Ha recibido tratamiento previo con algún otro fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un anticuerpo dirigido contra otros mecanismos o receptores inmunorreguladores. Ejemplos de anticuerpos de este tipo son, entre otros, anticuerpos contra IDO, PD-L1, IL-2R y GITR.
    - Tiene un diagnóstico de inmunodeficiencia o ha recibido esteroides sistémicos o alguna otra forma de tratamiento inmunodepresor en los siete días previos a días previos a la administración de la primera dosis del tratamiento del ensayo, excepto en caso de metástasis en el sistema nervioso central (SNC).
    - Padece una enfermedad autoinmunitaria activa con necesidad de tratamiento sistémico en los tres últimos meses o tiene antecedentes documentados de una enfermedad autoinmunitaria clínicamente grave o de un síndrome que requiera tratamiento sistémico o inmunodepresor.
    -Presenta otra neoplasia maligna conocida que está en progresión o que ha necesitado tratamiento activo en los tres últimos años.
    Nota: No se excluirá del estudio a los sujetos con carcinoma basocelular de piel, carcinoma espinocelular de piel que se haya sometido a un tratamiento potencialmente curativo o carcinoma in situ.
    - Presenta metástasis activas conocidas en el SNC o meningitis carcinomatosa.
    - Tiene antecedentes de neumonitis (no infecciosa) que precisó esteroides o una neumonitis activa.
    - Ha recibido un trasplante de órgano sólido previo.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate (ORR) per RECIST 1.1 by BCIR
    Tasa de respuestas objetivas (TRO) por RECIST 1.1 por RCIE
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Interim & Final Analyses. Interim Analysis to be conducted on the non clear cell RCC cohort and is to be performed at the time when 30th subject in this cohort has the opportunity to complete the 3rd scan
    En análisis final e intermedio. Se realizará un análisis intermedio de la cohorte con CR de células no claras cuando el trigésimo sujeto de esa cohorte haya tenido la oportunidad de someterse al tercer estudio de imagen.
    E.5.2Secondary end point(s)
    - Duration of response (DOR) per RECIST 1.1 by BCIR
    - Disease control rate (DCR) per RECIST 1.1 by BCIR
    - Progression-free survival (PFS) per RECIST 1.1 by BCIR; overall survival (OS)
    - Duración de la respuesta (DR) por RECIST 1.1 por RCIE
    - tasa de control de la enfermedad (TCE) por RECIST 1.1 por RCIE
    - progresión de la enfermedad (SSP) por RECIST 1.1 por RCIE; supervivencia global (SG)
    E.5.2.1Timepoint(s) of evaluation of this end point
    At Interim & Final Analyses
    En análisis intermedio y final
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA28
    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
    Canada
    Czech Republic
    Denmark
    Germany
    Korea, Republic of
    Poland
    Russian Federation
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LSLV: estimated 27Apr20
    LSLV: estimado 27Apr2020
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 135
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 115
    F.4.2.2In the whole clinical trial 255
    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)
    After confirmation of PD, subjects may initiate any subsequent anticancer treatment at the discretion of the treating physician and the subject per local standard of care.
    Tras la confirmación de la PE, los sujetos podrán iniciar cualquier tratamiento antineoplásico posterior a criterio del médico responsable del tratamiento y del sujeto con arreglo a la práctica local.
    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 Decision2016-09-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-04-01
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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