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    Summary
    EudraCT Number:2017-004387-35
    Sponsor's Protocol Code Number:MK-3475-775/E7080-G000-309
    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:2018-04-20
    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 number2017-004387-35
    A.3Full title of the trial
    A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination with Pembrolizumab Versus Treatment of Physician’s Choice in Participants with Advanced Endometrial Cancer
    Ensayo de fase 3, abierto, multicéntrico y aleatorizado para comparar la eficacia y la seguridad de lenvatinib en combinación con pembrolizumab frente al tratamiento de elección del médico en pacientes con cáncer de endometrio avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 study of lenvatinib plus pembrolizumab for advanced endometrial cancer
    Estudio de fase 3 de lenvatinib más pembrolizumab en el cáncer de endometrio avanzado
    A.4.1Sponsor's protocol code numberMK-3475-775/E7080-G000-309
    A.5.4Other Identifiers
    Name:IND NumberNumber:118,808
    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 SponsorEisai Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportEisai Ltd
    B.4.2CountryUnited Kingdom
    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 SA
    B.5.2Functional name of contact pointInvestigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressC/ Josela Valcárcel, 38
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28027
    B.5.3.4CountrySpain
    B.5.4Telephone number+34689859263
    B.5.5Fax number+3491 3210590
    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 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
    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: 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
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 DOXO-cell 150 mg solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holdercell pharm GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 injection
    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 INNDOXORUBICIN HYDROCHLORIDE
    D.3.9.1CAS number 25316-40-9
    D.3.9.4EV Substance CodeSUB01827MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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) 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 RoleComparator
    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 Paclitaxel Amneal 6 mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderAmneal Pharma Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 Concentrate for 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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) 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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 Concentrate for 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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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) 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: 7
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 injection
    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 INNDOXORUBICIN HYDROCHLORIDE
    D.3.9.1CAS number 25316-40-9
    D.3.9.4EV Substance CodeSUB01827MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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) 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.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
    Advanced Endometrial Cancer
    Cáncer de endometrio avanzado
    E.1.1.1Medical condition in easily understood language
    Advanced Endometrial Cancer [cancer of the lining of the uterus (or womb)]
    Cáncer endometrial avanzado [cáncer del revestimiento del útero (o útero)]
    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 10014733
    E.1.2Term Endometrial cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To demonstrate that lenvatinib in combination with pembrolizumab is superior to Treatment of Physician’s Choice (TPC) in improving progression-free survival (PFS).
    - To demonstrate that lenvatinib in combination with pembrolizumab is superior to TPC in improving overall survival (OS).
    - Demostrar que lenvatinib en combinación con pembrolizumab es superior al tratamiento de elección del médico (TEM) para mejorar la supervivencia sin progresión (SSP).
    - Demostrar que lenvatinib en combinación con pembrolizumab es superior al TEM para mejorar la supervivencia global (SG).
    E.2.2Secondary objectives of the trial
    - To compare the objective response rate (ORR) of participants treated with lenvatinib in combination with pembrolizumab versus TPC by BICR.
    - To evaluate the impact of treatment on Health-Related Quality of Life (HRQoL) as assessed by using the global score of the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 for participants treated with lenvatinib in combination with pembrolizumab versus TPC.
    - To assess safety and tolerability of treatment with lenvatinib in combination with pembrolizumab versus TPC in pMMR participants and in all-comer participants.
    - To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with pembrolizumab in pMMR participants and in all-comer participants.

    refer to protocol for complete list
    -Comparar la tasa de respuestas objetivas (TRO) entre las participantes tratadas con lenvatinib en combinación con pembrolizumab y las tratadas con TEM según una RCIE.
    -Evaluar la repercusión del tratamiento en la calidad de vida relacionada con la salud (CVRS), evaluada mediante la puntuación global en el cuestionario QLQ-C30 de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC) en las participantes tratadas con lenvatinib en combinación con pembrolizumab en comparación con el TEM.
    -Evaluar la seguridad y la tolerabilidad del tratamiento con lenvatinib en combinación con pembrolizumab en comparación con el TEM en las participantes con REEc y en todas las participantes.
    -Definir la farmacocinética (FC) poblacional de lenvatinib al administrarlo conjuntamente con pembrolizumab en las participantes con REEc y en todas las participantes.

    Consulte el protocolo para la lista completa
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically confirmed diagnosis of endometrial carcinoma.
    2. Documented evidence of advanced, recurrent or metastatic EC.
    3. Radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for recurrent, metastatic or primary unresectable disease.
    - Participants who progress <1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy are eligible without further systemic treatment.
    - Participants who progress ≥1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy must receive 1 additional cytotoxic systemic treatment prior to enrollment in this study.
    4. Available historical or fresh tumor biopsy specimen for determination of MMR status.
    5. At least 1 measurable target lesion according to RECIST 1.1 and confirmed by BICR, including the following criteria:
    - Non-nodal lesion that measures ≥1.0 cm in the longest diameter
    - Lymph node (LN) lesion that measures as ≥1.5 cm in the short axis
    - The lesion is suitable for repeat measurement using computed tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of subsequent growth.
    6. ECOG performance status of 0 or 1 within 3 days of starting study treatment.
    7. Female participants age ≥18 years and considered an adult per local regulations at the time of informed consent.
    8. 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 WOCBP
    OR
    b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
    9. The participant provides written informed consent for the study.
    10. 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 C1D1.
    11. Have adequate organ function. Specimens must be collected within 3 days prior to the start of study treatment.
    1. Diagnóstico de carcinoma de endometrio confirmado mediante histología.
    2. Datos documentados de CE avanzado, recurrente o metastásico.
    3. Signos radiológicos de progresión de la enfermedad después de recibir una pauta previa de quimioterapia sistémica basada en platino para la enfermedad recurrente, metastásica o primaria irresecable.
    - Las candidatas que presenten progresión < 1 año después de finalizar la quimioterapia adyuvante o neoadyuvante previa basada en platino podrán participar sin recibir más tratamiento sistémico.
    - Las candidatas que presenten progresión ≥ 1 año después de finalizar la quimioterapia adyuvante o neoadyuvante previa basada en platino deberán recibir un tratamiento sistémico citotóxico adicional antes de ser incluidas en este estudio.
    4. Muestra tumoral histórica disponible o muestra de biopsia tumoral reciente para determinar el estado relativo a la REE.
    5. Al menos una lesión diana mensurable conforme a los criterios RECIST, versión 1.1, y confirmada mediante una RCIE, incluidos los criterios siguientes:
    - Lesión no ganglionar que mide ≥ 1,0 cm de diámetro mayor.
    - Lesión ganglionar que mide ≥ 1,5 cm de eje menor.
    - La lesión es adecuada para obtener mediciones repetidas mediante tomografía computarizada/resonancia magnética (TC/RM). Las lesiones que hayan sido objeto de radioterapia externa (RTE) o tratamiento locorregional deben mostrar signos radiológicos de crecimiento posterior.
    6. Estado funcional del ECOG de 0 o 1 en los tres días previos al comienzo del tratamiento del estudio.
    7. Mujeres de 18 años de edad en adelante que sean consideradas adultas según las normas locales en el momento de obtención del consentimiento informado.
    8. Una mujer podrá participar en el estudio si no está embarazada (véase el apéndice 2), no está amamantando y cumple al menos una de las condiciones siguientes:
    a) No es una mujer en edad fértil (MEF) según se define en el apéndice 2.
    O bien
    b) Es una MEF que se compromete a seguir las normas relativas a métodos anticonceptivos indicadas en el apéndice 2 durante el período de tratamiento y hasta, como mínimo, 120 días después de la última dosis del tratamiento del estudio.
    9. La participante otorga su consentimiento informado por escrito para el estudio.
    10. Presión arterial (PA) debidamente controlada, con o sin antihipertensivos, definida como una PA ≤ 150/90 mm Hg en el período de selección y sin modificaciones de la medicación antihipertensiva en la semana previa al D1C1.
    11. Presencia de una función orgánica adecuada, tal como se define en la tabla 1. Las muestras se obtendrán en los tres días previos al comienzo del tratamiento del estudio.
    E.4Principal exclusion criteria
    1. Carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas.
    2. Participants with CNS metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
    3. Active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas, or basal or squamous cell carcinoma of the skin) within the past 24 months.
    4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
    5. 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.
    6. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
    7. 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 stroke, or cardiac arrhythmia associated with hemodynamic instability.
    8. Active infection (any infection requiring systemic treatment).
    9. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
    10. Participants known to be positive for Human Immunodeficiency Virus (HIV). No HIV testing is required unless mandated by local heath authority.
    11. Known active Hepatitis B or Hepatitis C. No testing for hepatitis B or C is required unless mandated by local health authority.
    12. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis.
    13. 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 to participate, in the opinion of the treating investigator.
    14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
    15. 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 to the first dose of study drug.
    16. Active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
    17. Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    18. Greater than 1 prior systemic anticancer regimen (other than adjuvant or neoadjuvant) for advanced, recurrent, or metastatic endometrial cancer.
    19. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter). All acute toxicities related to prior treatments must be resolved to Grade ≤1, except for alopecia and Grade ≤2 peripheral neuropathy.
    20. Prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

    Refer to protocol for complete list
    1. Carcinosarcoma (tumor mulleriano mixto maligno), leiomiosarcoma endometrial y sarcoma del estroma endometrial.
    2. Las participantes con metástasis en el SNC no podrán participar, a menos que hayan completado el tratamiento local (p. ej., radioterapia panencefálica [RPE], cirugía o radiocirugía) y hayan suspendido el uso de corticoides para esta indicación durante al menos cuatro semanas antes de iniciar el tratamiento del estudio. Todos los signos (p. ej., radiológicos) o síntomas de metástasis cerebrales deberán permanecer estables durante al menos cuatro semanas antes de iniciar el tratamiento del estudio.
    3. Neoplasia maligna activa (excepto cáncer de endometrio, carcinomas in situ tratados definitivamente [p. ej., mama, cuello uterino o vejiga], o carcinoma basocelular o espinocelular de piel) en los últimos 24 meses.
    4. Malabsorción gastrointestinal, anastomosis gastrointestinal o cualquier otra afección que pueda afectar a la absorción de lenvatinib.
    5. Signos radiológicos de invasión/infiltración de vasos sanguíneos importantes. El grado de invasión/infiltración tumoral de vasos sanguíneos importantes debe tenerse en cuenta debido al posible riesgo de hemorragia grave asociada a una reducción o necrosis tumoral después del tratamiento con lenvatinib.
    6. Hemoptisis o hemorragia tumoral clínicamente significativas en las dos semanas previas a la primera dosis del fármaco del estudio.
    7. Insuficiencia cardiovascular significativa en los 12 meses previos a la primera dosis del fármaco del estudio: antecedentes de insuficiencia cardíaca congestiva en clase superior a la II según la New York Heart Association (NYHA), angina inestable, infarto de miocardio, accidente cerebrovascular (ACV) o arritmia cardíaca asociada a inestabilidad hemodinámica.
    8. Infección activa (cualquier infección que requiera tratamiento sistémico).
    9. Participantes que no se hayan recuperado debidamente de cualquier toxicidad y/o complicación de una intervención de cirugía mayor antes de iniciar el tratamiento.
    10. Participantes con infección conocida por el virus de la inmunodeficiencia humana (VIH). No es necesario realizar pruebas de VIH a menos que lo exijan las autoridades sanitarias locales.
    11. Hepatitis B activa (por ejemplo, reactividad del HBsAg) o hepatitis C (por ejemplo, detección de ARN del VHC [cualitativo]) conocida. No es necesario realizar pruebas de hepatitis B o C a menos que lo exijan las autoridades sanitarias locales.
    12. Antecedentes de neumonitis (no infecciosa) que precisó tratamiento con esteroides o presencia de una neumonitis activa.
    13. 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 la participante.
    14. Presencia de un trastorno psiquiátrico o por abuso de sustancias que pueda dificultar el cumplimiento de los requisitos del ensayo.
    15. Diagnóstico de inmunodeficiencia o recepción de tratamiento sistémico crónico con esteroides (en dosis superiores a 10 mg diarios de prednisona o un equivalente) o cualquier otra forma de tratamiento inmunodepresor en los siete días previos a la primera dosis del fármaco del estudio.
    16. Enfermedad autoinmunitaria activa (con la excepción de psoriasis) que ha precisado tratamiento sistémico en los dos últimos años (es decir, uso de fármacos modificadores de la enfermedad, corticoides o inmunodepresores). El tratamiento de reposición (por ejemplo, tiroxina, insulina o corticoides fisiológicos por insuficiencia suprarrenal o hipofisaria) no se considera una forma de tratamiento sistémico.
    17. Mujeres lactantes o embarazadas en la visita de selección o basal (documentada mediante una determinación positiva de β-gonadotropina coriónica humana [β-hCG] (o hCG) con una sensibilidad mínima de 25 UI/l o unidades equivalentes de β-hCG [o hCG]). Se requiere una evaluación basal independiente si la prueba de embarazo de selección es negativa más de 72 horas antes de la primera dosis del fármaco del estudio.
    18. Más de un tratamiento antineoplásico sistémico previo (distinto de adyuvante o neoadyuvante) para el cáncer de endometrio avanzado, recurrente o metastásico.
    19. Tratamiento antineoplásico previo en un plazo de 28 días (o el equivalente a 5 veces la semivida, lo que suponga menos tiempo). Todos los efectos tóxicos agudos relacionados con los tratamientos previos deben haberse resuelto a un grado ≤ 1, excepto la alopecia y la neuropatía periférica de grado ≤ 2.
    20. Tratamiento previo con cualquier fármaco que actúe sobre la angiogénesis dirigida por el VEGF o con cualquier anticuerpo anti-PD-1, anti-PD-L1 o anti-PD-L2.

    Consulte el protocolo para la lista completa
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival: defined as the time from the date of randomization to the date of the first documentation of disease progression, as determined by blinded BICR of objective radiographic disease progression per RECIST 1.1 or death due to any cause(whichever occurs first).

    Overall Survival: defined as the time from the date of randomization to the date of death due to any cause. Participants who are lost to follow-up and those who are alive at the date of data cut-off will be censored at the date the participant was last known alive, or date of data cut-off, whichever occurs first.
    Supervivencia sin progresión: definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha de la primera documentación de progresión de la enfermedad, determinada mediante una revisión central independiente y enmascarada (RCIE) conforme a los Criterios de evaluación de la respuesta en tumores sólidos (RECIST), versión 1.1, o la muerte por cualquier causa, lo que antes ocurra.

    Supervivencia global: definida como el tiempo transcurrido entre la fecha de aleatorización y la fecha de la muerte por cualquier causa. Las pacientes cuyo seguimiento se ha perdido y las que están vivas en la fecha de corte de datos serán censuradas, en la fecha en que se supo que la participante estaba viva o la fecha de corte de datos, lo que antes ocurra.
    E.5.1.1Timepoint(s) of evaluation of this end point
    An interim analysis for superiority of OS is planned for the study. The interim analysis will be conducted when there are approximately 363 death events observed in the pMMR participants, which is estimated to occur approximately 27 months after the first participant is randomized for the pMMR participants. The final PFS analysis is to occur at the time of the OS interim analysis.

    refer to protocol for complete list
    Se planea un análisis intermedio para evaluar la SG para el estudio. El análisis intermedio se llevará a cabo cuando cuando haya aproximadamente 363 eventos de muerte observados en las participantes con REEc, lo que se estima que ocurrirá aproximadamente 27 meses después de que la primera participante sea aleatorizada, para los participantes con REEc. El análisis final de la SSP debe ocurrir al mismo tiempo que el análisis provisional de la SG.


    Consulte el protocolo para la lista completa
    E.5.2Secondary end point(s)
    - Objective response rate (ORR) by BICR using RECIST 1.1.
    - Health-Related Quality of Life using the EORTC QLQ-C30.
    - Safety and tolerability of the two treatment groups.
    - Plasma concentration of lenvatinib versus time.
    - Model-predicted clearance and AUC for lenvatinib.
    - Tasa de respuesta objetiva (TRO) según una RCIE usando RECIST 1.1
    - Calidad de vida relacionada con la salud usando el cuestionario QLQ-C30 de la EORTC
    - Seguridad y tolerabilidad de los dos grupos de tratamiento
    - Concentración plasmática de lenvatinib en función del tiempo
    - Aclaramiento y AUC de lenvatinib previstos por el modelo
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoints will be evaluated at the final analysis and as required during the interim analysis.
    Los criterios de valoración secundarios serán evaluados en el análisis final y según se requiera durante el análisis intermedio.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA49
    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
    Brazil
    Canada
    Colombia
    France
    Germany
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Poland
    Russian Federation
    Spain
    Taiwan
    Turkey
    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
    The overall study ends when the last participant completes the last study-related telephone-call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be contacted by the investigator).
    El estudio en su conjunto finalizará cuando la última participante complete la última llamada telefónica o visita del estudio, se retire del estudio o se pierda para el seguimiento (es decir, cuando el investigador no pueda ponerse en contacto con la participante).
    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 years3
    E.8.9.2In all countries concerned by the trial months7
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 600
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 225
    F.4.2.2In the whole clinical trial 780
    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)
    There is no study-specified treatment following the end of the study.
    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 Decision2018-06-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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