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    Summary
    EudraCT Number:2017-003134-85
    Sponsor's Protocol Code Number:MK-3475-495
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2018-10-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2017-003134-85
    A.3Full title of the trial
    A Phase 2 Precision Oncology Study of Biomarker-Directed, Pembrolizumab- (MK-3475, SCH 900475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (KEYNOTE-495; KeyImPaCT)
    Estudio de oncología de precisión de fase 2 para evaluar el tratamiento combinado basado en pembrolizumab (MK-3475, SCH 900475) dirigido a biomarcadores en el cáncer de pulmón no microcítico avanzado (KEYNOTE-495; KeyImAmpCT).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Pembrolizumab Combination Therapy for Advanced Non-Small Cell Lung Cancer
    Estudio combinado basado en pembrolizumab dirigido a biomarcadores en el cáncer de pulmón no microcítico avanzado
    A.3.2Name or abbreviated title of the trial where available
    KeyImPaCT: Keytruda Immunotherapy Personalized and Combination Treatment
    KeyImPaCT: Tratamiento personalizado y combinado con inmunoterapia con Keytruda
    A.4.1Sponsor's protocol code numberMK-3475-495
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03516981
    A.5.4Other Identifiers
    Name:EISAINumber:E7080-G000-223
    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+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 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.3.2Product code MK-4280
    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 INNNot available
    D.3.9.3Other descriptive nameMK-4280
    D.3.9.4EV Substance CodeSUB191937
    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: 3
    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 Kisplyx
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe 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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENVATINIB MESILATE
    D.3.9.1CAS number 857890-39-2
    D.3.9.3Other descriptive nameLENVATINIB MESILATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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: 4
    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 Kisplyx
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe 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.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENVATINIB MESILATE
    D.3.9.1CAS number 857890-39-2
    D.3.9.3Other descriptive nameLENVATINIB MESILATE
    D.3.9.4EV Substance CodeSUB72971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    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: 5
    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.3.2Product code L01XC18
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of advanced NSCLC
    Tratamiento del CPNM avanzado
    E.1.1.1Medical condition in easily understood language
    Advanced Non-small cell lung cancer
    cáncer de pulmón no microcítico avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029522
    E.1.2Term Non-small cell lung cancer stage IV
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical activity (as assessed by objective response rate [ORR]) of specific pembrolizumab-based combinations.
    Evaluar la actividad clínica (determinada mediante la tasa de respuestas objetivas [TRO]) de combinaciones específicas basadas en pembrolizumab.
    E.2.2Secondary objectives of the trial
    1) To evaluate the clinical activity (as assessed by progression-free survival [PFS] and overall survival [OS]) of specific pembrolizumab-based combinations. PFS and OS to different specific pembrolizumab-based combinations will be assessed independently in each biomarker-defined group
    2) To determine the safety and tolerability of pembrolizumab in combination with either MK- 4280, or lenvatinib. Safety and tolerability to different specific pembrolizumab-based combinations will be assessed independently in each biomarker-defined group
    1)Evaluar la actividad clínica (determinada mediante la supervivencia sin progresión [SSP] y la supervivencia global [SG]) de combinaciones específicas basadas en pembrolizumab. La SSP y la SG con diferentes combinaciones específicas basadas en pembrolizumab se evaluarán de forma independiente en cada grupo definido por biomarcadores.
    2)Determinar la seguridad y la tolerabilidad de pembrolizumab en combinación con MK-4280 o lenvatinib. La seguridad y la tolerabilidad de diferentes combinaciones específicas basadas en pembrolizumab se evaluarán de forma independiente en cada grupo definido por biomarcadores.
    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, RNA and tumor 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 en las muestras de ADN , ARN y tumor recogidas durante este ensayo clínico. Dichas 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 serán llevados a cabo con muestras de 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
    1.Have a histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v. 8) NSCLC and study participants should not have had prior systemic therapy for advanced disease.
    2. Have confirmation that epidermal growth factor receptor– (EGFR-),anaplastic lymphoma kinase– (ALK-), c-ros oncogene 1 (ROS1), or Bisoform of rapidly accelerated fibrosarcoma (B-Raf) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR or B-Raf mutations AND absence of ALK or ROS1 gene rearrangements). If participant's tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
    3. Have measurable disease per RECIST 1.1 as assessed by the local site
    investigator/radiology. Lesions situated in a previously irradiated area
    are considered measurable if progression has been demonstrated in such lesions.
    4. Male/female subjects who are at least 18 years of age on the day of
    signing the informed consent.
    5. A male participant must agree to use a contraceptive as detailed in the protocol 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.
    6. A female participant is eligible to participate if she is not pregnant,
    not breastfeeding, and at least one of the following conditions applies:
    a.) Not a woman of childbearing potential (WOCBP)
    OR
    b.) A WOCBP who agrees to follow the contraceptive guidance in the
    protocol during the treatment period and for at least 120 days after the
    last dose of study treatment.
    7. The participant (or legally acceptable representative if applicable)
    provides written informed consent for the study. The participant may
    also provide consent for Future Biomedical Research. However, the
    participant may participate in the main study without participating in
    Future Biomedical Research.
    8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Newly
    obtained biopsies are preferred to archival tissue. Repeat samples may
    be required if adequate tissue is not provided.
    9. Participants must have adequately controlled blood pressure (BP)
    with or without antihypertensive medications, defined as BP ≤150/90
    mm Hg at Screening and no change in antihypertensive medications
    within 1 week before Cycle 1/Day 1.
    10. Have an Eastern Cooperative Oncology Group (ECOG) performance
    status of 0 to 1.
    11. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment.
    1. Diagnóstico confirmado histológica o citológicamente de CPNM en estadio IV (American Joint Committee on Cancer [AJCC], versión 8) y ausencia de tratamiento sistémico previo para la enfermedad avanzada.
    2. Confirmación de que el tratamiento dirigido contra el receptor del factor de crecimiento epidérmico (EGFR), la cinasa del linfoma anaplásico (ALK), el oncogén c-ros 1 (ROS1), o la isoforma B del fibrosarcoma acelerado rápidamente (B-Raf) no está indicado como tratamiento primario (documentación de la ausencia de mutaciones activadoras de EGFR o B-Raf Y de reordenamientos del gen ALK o ROS1 en el tumor). Cuando se sepa que el tumor del participante tiene una histología predominantemente epidermoide no será necesario realizar análisis moleculares para identificar mutaciones de EGFR y translocaciones de ALK y ROS1, ya que ello no forma parte de las directrices diagnósticas actuales.
    3. Presencia de enfermedad mensurable conforme a los criterios RECIST 1.1, según la evaluación del investigador/radiólogo del centro. Las lesiones ubicadas en una zona previamente irradiada se considerarán mensurables siempre que se haya constatado progresión en dichas lesiones.
    4. Participante de cualquier sexo con una edad mínima de 18 años el día de firma del consentimiento informado.
    5. Los varones deben comprometerse a utilizar métodos anticonceptivos tal como se detalla en este protocolo 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.
    6. Una mujer podrá participar en el estudio si no está embarazada, no está amamantando y cumple al menos una de las condiciones siguientes:
    a.) No es una mujer en edad fértil (MEF)
    O
    b.) Es una MEF que se compromete a seguir las normas relativas a métodos anticonceptivos indicadas en el protocolo durante el período de tratamiento y hasta, como mínimo, 120 días después de la última dosis del tratamiento del estudio.
    7. El participante (o su representante legal cuando proceda) otorga su consentimiento informado por escrito para el estudio. El participante también podrá otorgar su consentimiento para las investigaciones biomédicas futuras. No obstante, podrá participar en el estudio principal sin necesidad de hacerlo en las investigaciones biomédicas futuras.
    8. Disponibilidad de una muestra de tejido tumoral de archivo o de una biopsia reciente, con aguja gruesa o por escisión, de una lesión tumoral no irradiada previamente. Se prefiere el uso de biopsias recientes al tejido de archivo. Podrían necesitarse nuevas muestras en caso de que no se disponga de tejido suficiente.
    9. Presión arterial (PA) adecuadamente controlada con o sin medicación antihipertensiva, lo que se define como PA < 150/90 mm Hg en la selección y sin modificaciones de la medicación antihipertensiva durante al menos una semana antes del día 1 del ciclo 1.
    10. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 a 1.
    11. Presencia de una función orgánica adecuada, que se define en el protocolo. Las muestras se obtendrán en los 10 días previos al comienzo del tratamiento del estudio
    E.4Principal exclusion criteria
    1. Has significant cardiovascular impairment within 12 months of the
    first dose of study drug: such as history of congestive heart failure
    greater than NYHA Class II, unstable angina, myocardial infarction or
    cerebrovascular accident (CVA) stroke, cardiac arrhythmia associated
    with hemodynamic instability, or a left ventricular ejection fraction
    (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram.
    2. Prolongation of QTc interval to >480 ms.
    3. Has symptomatic ascites or pleural effusion. A participant who is
    clinically stable following treatment for these conditions is eligible.
    4. Has had an allogenic tissue/solid organ transplant.
    5. A WOCBP who has a positive urine pregnancy test within 72 hours
    before the first dose of study treatment.
    6. Subjects with proteinuria >1+ on urine dipstick testing will undergo
    24-hour urine collection for quantitative assessment of proteinuria.
    Subjects with urine protein ≥1 g/24 h will be ineligible.
    7. Subjects who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
    8. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any
    other condition that might affect the absorption of lenvatinib
    9. Radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage
    associated with tumor shrinkage/necrosis following lenvatinib therapy.
    10. Clinically significant hemoptysis or tumor bleeding within 2 weeks
    prior to the first dose of study drug.
    11. Has received prior systemic chemotherapy treatment for
    metastatic/recurrent NSCLC.
    12. Has current NSCLC disease that can be treated with curative intent
    with surgical resection, localized radiotherapy, or chemoradiation.
    13. Is expected to require any other form of systemic or localized
    antineoplastic therapy while on study.
    14. 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 coinhibitory T cell receptor (eg, CTLA-4, OX 40, CD137).
    15. Has received previous treatment with another agent targeting the
    LAG3 receptor.
    16. Has received previous treatment with another agent targeting VEGF
    or the VEGF receptor.
    17. Has received prior anticancer therapy including investigational
    agents within 4 weeks prior to randomization.
    18. Has received prior radiotherapy within 3 weeks of start of study
    treatment.
    19. Has received a live vaccine within 30 days prior to the first dose of
    study treatment.
    20. 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 treatment.
    21. 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 treatment.
    22. Has a known additional malignancy that is progressing or has
    required active treatment within the past 3 years.
    23. Has known active CNS metastases and/or carcinomatous meningitis.
    24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, MK-4280,
    or lenvatinib and/or any of its excipients.
    25. Has an active autoimmune disease that has required systemic
    treatment in past 2 years (ie, with use of disease modifying agents,
    corticosteroids, or immunosuppressive drugs). Replacement therapy is
    not considered a form of systemic treatment and is allowed.
    26. Has a history of (noninfectious) pneumonitis that required steroids
    or has current pneumonitis.
    27. Has an active infection requiring systemic therapy.
    28. Has a known history of human immunodeficiency virus (HIV)
    infection. No HIV testing is required unless mandated by local health
    authority.
    29. Has a known history of hepatitis B (defined as hepatitis B surface
    antigen [HBsAg] reactive) or known active hepatitis C virus (defined as
    HCV RNA [qualitative] is detected) infection.
    1. Presencia de un trastorno cardiovascular importante en los 12 meses previos a la primera dosis del fármaco del estudio, como antecedentes de insuficiencia cardíaca congestiva en clase II según la New York Heart Association (NYHA), angina inestable, infarto de miocardio o accidente cerebrovascular (ACV) o ictus, arritmia cardíaca asociada a inestabilidad hemodinámica o fracción de eyección del ventrículo izquierdo (FEVI) por debajo del intervalo normal del centro determinada mediante ventriculografía isotópica en equilibrio (MUGA) o ecocardiograma.
    2. Prolongación del intervalo QTc a >480 ms
    3. Presencia de ascitis o derrame pleural sintomático. Podrán participar sujetos que se encuentren clínicamente estables tras recibir tratamiento por estos procesos
    4. Recepción de un alotrasplante de órgano sólido/tejidos.
    5. Mujer en edad fértil que da positivo en una prueba de embarazo en orina realizada en las 72 horas previas a la primera dosis del tratamiento del estudio.
    6. Los sujetos con proteinuria > 1+ en el análisis de orina con tira reactiva se someterán a una recogida de orina de 24 horas para una evaluación cuantitativa de la proteinuria. Los sujetos con proteinuria > 1 g/24 h no podrán participar.
    7. Sujetos que no se hayan recuperado debidamente de cualquier toxicidad y/o complicación de una intervención de cirugía mayor antes de iniciar el tratamiento.
    8. Malabsorción gastrointestinal, anastomosis gastrointestinal o cualquier otra afección que pueda afectar a la absorción de lenvatinib.
    9. Evidencia radiográfica de invasión/infiltración tumoral de los principales vasos sanguíneos. El grado de invasión/infiltración tumoral de los principales vasos sanguíneos debe tenerse en cuenta debido al posible riesgo de hemorragia grave asociada a una reducción/necrosis tumoral después del tratamiento con lenvatinib.
    10. Hemoptisis clínicamente significativa o hemorragia tumoral en las dos semanas previas a la primera dosis del fármaco del estudio
    11. Recepción de quimioterapia sistémica previa por CPNM metastásico/recurrente.
    12. Presencia de un CPNM que puede tratarse con fines curativos mediante resección quirúrgica, radioterapia localizada o quimiorradioterapia.
    13. Previsión de necesitar cualquier otra forma de tratamiento antineoplásico sistémico o localizado durante el estudio.
    14. Recepción de un tratamiento previo con un fármaco anti-PD-1, anti-PD-L1 o anti-PD-L2 o con un fármaco dirigido contra otro receptor de los linfocitos T estimulador o coinhibidor (como CTLA-4, OX-40 o CD137).
    15. Recepción de un tratamiento previo con otro fármaco dirigido contra el receptor de LAG3.
    16. Recepción de un tratamiento previo con otro fármaco dirigido contra VEGF o el receptor de VEGF.
    17. Recepción de un tratamiento antineoplásico previo, incluidos fármacos en investigación, en las cuatro semanas previas a la aleatorización.
    18. Recepción de radioterapia en las tres semanas previas al comienzo del tratamiento del estudio.
    19. Recepción de una vacuna de microorganismos vivos en los 30 días previos a la administración de la primera dosis del tratamiento del estudio.
    20. 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 del tratamiento del estudio.
    21. 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 tratamiento del estudio.
    22. Presencia de otra neoplasia maligna conocida que está en progresión o ha precisado tratamiento activo en los últimos tres años.
    23. Presencia de metástasis activas en el SNC y/o de meningitis carcinomatosa.
    24. Presencia de hipersensibilidad grave (grado > 3) a pembrolizumab, MK-4280 o lenvatinib y/o a cualquiera de sus excipientes.
    25. Presencia de una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico (es decir, fármacos modificadores de la enfermedad, corticoides o inmunodepresores) en los dos últimos años. El tratamiento de reposición no se considera una forma de tratamiento sistémico y se permitirá su uso.
    26. Antecedentes de neumonitis (no infecciosa) que precisó la administración de esteroides o presencia de una neumonitis activa.
    27. Presencia de una infección activa que precisa tratamiento sistémico.
    28. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH). No es necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
    29. Antecedentes de infección por el virus de la hepatitis B (reactividad del antígeno de superficie del virus de la hepatitis B [HBsAg]) o de infección activa por el virus de la hepatitis C (definida como detección de ARN del virus de la hepatitis C [VHC] [cualitativo]).
    E.5 End points
    E.5.1Primary end point(s)
    objective response rate (ORR) based on RECIST 1.1 as assessed by local site review
    La tasa de respuesta objetiva (TRO) basada en los criterios RECIST 1.1 determinada por la revisión del centro
    E.5.1.1Timepoint(s) of evaluation of this end point
    ORR will be used at interim analysis and first database lock
    La tasa de respuestas objetivas (TRO) será utilizado en los análisis intermedios y el primer corte de datos
    E.5.2Secondary end point(s)
    1. PFS based on RECIST 1.1 as assessed by local site review
    2. OS
    3. Safety as assessed by the number of participants experiencing AEs and the number of participants discontinuing study drug due to AEs.
    1. La Supervivencia sin progresión basada en los criterios RECIST 1.1 determinada por la revisión del centro
    2. Supervivencia global
    3. Seguridad según sea determinada por el número de participantes que experimenten acontecimientos adversos (AAs) y el número de participantes que discontinúen el fármaco del estudio debido a los AAs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be analysed at final database lock
    Los objetivos secundarios se analizarán en el corte de datos final
    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 Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Diseño de aleatorización adaptativa
    Adaptive randomization design
    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.8.2.4Number 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA43
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    France
    Hong Kong
    Ireland
    Italy
    Korea, Republic of
    Poland
    Russian Federation
    Singapore
    South Africa
    Spain
    Switzerland
    Taiwan
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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 years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 96
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 96
    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 state22
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 101
    F.4.2.2In the whole clinical trial 192
    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 the end of treatment, each participant will be followed for the occurrence of AEs and pregnancy. Participants who discontinue for reasons other than disease progression will have follow-up imaging until documented disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. All participants will be followed by telephone for OS until death,withdrawal of consent, or the end of the study.
    Al final del tto. se hará seguimiento por efectos adversos y embarazos. Pacientes que hayan discontinuado por otras razones que no sean progresión de la enfermedad tendrán seguimiento por imágenes hasta que haya progreso de la enfermedad documentado, inicien otro tto. antineoplásico fuera de estudio, retiren su consentimiento informado, o se pierda su seguimiento. Los sujetos tendrán un seguimiento de supervivencia telefónico hasta su fallecimiento, retirada del consentimiento o fin de 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 Decision2018-11-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-05
    P. End of Trial
    P.End of Trial StatusRestarted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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