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    Summary
    EudraCT Number:2016-002778-11
    Sponsor's Protocol Code Number:E7080-G000-218
    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:2017-05-26
    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 number2016-002778-11
    A.3Full title of the trial
    A Randomized, Double-blind, Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs. 14 mg QD) in Combination with Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
    Ensayo de fase 2, aleatorizado y doble ciego para evaluar la seguridad y la eficacia de lenvatinib en dos dosis iniciales diferentes (18 mg y 14 mg una vez al día) en combinación con everolimus (5 mg una vez al día) en carcinoma de células renales después de un tratamiento previo dirigido contra el VEGF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Double-blind, Phase 2 Trial to assess how safe and how efficacious Lenvatinib is at two different starting doses (18 mg vs. 14 mg QD) when it is given in Combination with Everolimus (5 mg once a day ) in patients with Renal cancer that have already had one VEGF-Targeted Treatment
    Ensayo de fase 2, aleatorizado y doble ciego para evaluar la seguridad y la eficacia de lenvatinib en dos dosis iniciales diferentes (18 mg y 14 mg una vez al día) cuando se administra en combinación con everolimus (5 mg una vez al día) en pacientes con cáncer renal después de un tratamiento previo dirigido contra el VEGF
    A.4.1Sponsor's protocol code numberE7080-G000-218
    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 supportEisai Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Europe Ltd
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressEMEA Knowledge Centre, Mosquito Way
    B.5.3.2Town/ cityHatfield
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+34900834223
    B.5.6E-mailRegistroespanoldeestudiosclinicos@druginfo.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 Kisplyx 4 mg
    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.3.1Product nameLenvatinib
    D.3.2Product code E7080
    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 417716-92-8
    D.3.9.2Current sponsor codeE7080
    D.3.9.3Other descriptive nameLENVATINIB
    D.3.9.4EV Substance CodeSUB64419
    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: 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 10 mg
    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.3.1Product nameLenvatinib
    D.3.2Product code E7080
    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 417716-92-8
    D.3.9.2Current sponsor codeE7080
    D.3.9.3Other descriptive nameLENVATINIB
    D.3.9.4EV Substance CodeSUB64419
    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: 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 Afinitor 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharma Limited
    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 nameAfinitor
    D.3.4Pharmaceutical form Tablet
    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 INNEverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Advanced renal cell carcinoma
    Carcinoma renal avanzado
    E.1.1.1Medical condition in easily understood language
    kidney cancer that has advanced and tumours are getting bigger
    Cáncer de riñón que ha progresado y cuyos tumores se están agrandando
    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 10038389
    E.1.2Term Renal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10038409
    E.1.2Term Renal cell carcinoma NOS
    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 assess whether a starting dose of lenvatinib 14 mg in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR]at 24 weeks[ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment emergent intolerable Grade 2, or any ≥ Grade 3 adverse events (AEs) in the first 24 weeks after randomization).
    Evaluar si una dosis inicial de 14 mg de lenvatinib en combinación con 5 mg de everolimus una vez al día (1 v/d) proporcionará una eficacia similar (basada en la tasa de respuesta objetiva [TRO] a las 24 semanas [TRO24S]) con un mejor perfil de seguridad en comparación con 18 mg de lenvatinib en combinación con 5 mg de everolimus (en función de los acontecimientos adversos [AA] aparecidos durante el tratamiento de grado 2 intolerables o cualquiera de grado >= 3 en las primeras 24 semanas después de la aleatorización).
    E.2.2Secondary objectives of the trial
    To assess progression-free survival (PFS).
    To assess ORR.
    To determine the tolerability and safety profile of lenvatinib in combination with everolimus.
    To assess the proportion of subjects who discontinued treatment due to toxicity.
    To assess time to treatment failure due to toxicity.
    To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during combination therapy and to assess PK and pharmacodynamic (PD) drug-drug interactions.
    To evaluate overall survival (OS).
    To evaluate the impact of disease and treatment on patients' Health-Related Quality of Life (HRQoL) as assessed by using the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of Life (EuroQol) EQ-5D-3L.
    To evaluate the PFS after next line of treatment (PFS2).
    -Evaluar la supervivencia libre de progresión (SLP).
    -Evaluar la TRO.
    -Determinar el perfil de tolerabilidad y seguridad de lenvatinib en combinación con everolimus.
    -Evaluar la proporción de sujetos que suspendan el tratamiento por toxicidad.
    -Evaluar el tiempo hasta el fracaso del tratamiento por toxicidad.
    -Evaluar los perfiles farmacocinéticos (FC) de lenvatinib y everolimus durante el tratamiento de combinación y las interacciones farmacológicas FC y farmacodinámicas (FD).
    -Evaluar la supervivencia global (SG).
    -Evaluar la repercusión de la enfermedad y el tratamiento en la calidad de vida relacionada con la salud (CdVRS) de los pacientes mediante la Evaluación funcional de la terapia contra el cáncer - índice de síntomas renales - síntomas relacionados con la enfermedad (FKSI-DRS), el cuestionario QLQ-C30 de la EORTC y el cuestionario EQ-5D-3L del Grupo europeo de calidad de vida (EuroQol).
    -Evaluar la SLP después de la siguiente línea de tratamiento (SLP2).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis of RCC is acceptable).
    2. Documented evidence of advanced RCC.
    3. One prior disease progression episode on or after VEGF-targeted treatment (for example, but not limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib) administered for the treatment of RCC. Prior PD-1/PD-L1 treatment in addition to 1 prior VEGF-targeted treatment is allowed.
    4. At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria:
    Lymph node (LN) lesion that measures at least 1 dimension as ≥1.5 cm in the short axis Non-nodal lesion that measures ≥1.0 cm in the longest diameter
    The lesion is suitable for repeat measurement using computerized tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
    5. Male or female subjects age ≥18 years (or any age >18 years if that age is considered to be an adult per the local jurisdiction) at the time of informed consent.
    6. Karnofsky Performance Status (KPS) of ≥70.
    7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week before Cycle 1/Day 1.
    8. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft and Gault formula (Appendix 1).
    9. Adequate bone marrow function defined by:
    Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 109/L) Platelets ≥100,000/mm3(≥100 x 109/L) Hemoglobin ≥9 g/dL.
    10. Adequate blood coagulation function defined by International Normalized Ratio (INR) ≤1.5 (except for subjects on warfarin therapy where INR must be ≤3.0 prior to randomization).
    11. Adequate liver function defined by:
    Total bilirubin ≤1.5 times the ULN except for unconjugated hyperbilirubinemia of Gilbert’s syndrome.
    Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN). Subjects with bone metastases with ALP values greater than 3 times can be included.
    12. Subject must voluntarily agree to provide written informed consent.
    13. Subject must be willing and able to comply with all aspects of the protocol.
    1.Confirmación histológica o citológica de CCR con predominio de células claras (es admisible el diagnóstico tisular original de CCR).
    2.Pruebas documentadas de CCR avanzado.
    3.Un episodio de progresión de la enfermedad previo durante o después del tratamiento dirigido al VEGF (p. ej., sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/tivozanib, entre otros) administrado para el tratamiento del CCR. Está permitido el tratamiento previo contra PD-1/PD-L1 además de un tratamiento previo dirigido contra el VEGF.
    4.Al menos una lesión diana medible según los RECIST 1.1 que cumpla los siguientes criterios:
    -Lesión en un ganglio linfático (GL) en la que al menos una dimensión mida >=1,5 cm en el eje corto
    -Lesión no ganglionar que mida >= 1,0 cm en el diámetro más largo.
    -La lesión es adecuada para mediciones repetidas mediante tomografía computarizada (TC) o resonancia magnética (RM). Para que se consideren lesiones diana, las lesiones que se hayan sometido a radioterapia externa (RTE) o a tratamientos locorregionales deberán mostrar signos radiológicos de progresión de la enfermedad según la versión 1.1 de los RECIST.
    5.Sujetos hombres y mujeres de 18 años de edad en adelante (o de cualquier edad superior a los 18 años que se considere la mayoría de edad según la jurisdicción local) en el momento de la firma del consentimiento informado.
    6.Puntuación del estado general según la escala de Karnofsky (KPS) >= 70.
    7.Presión arterial (PA) debidamente controlada con o sin antihipertensores, definida como una PA <= 150/90 mm Hg en la selección y ausencia de cambios en el tratamiento antihipertensor en la semana previa al día 1 del ciclo 1.
    8.Función renal adecuada, definida como un aclaramiento de creatinina calculado ≥30 ml/min según la ecuación de Cockcroft y Gault
    9.Función adecuada de la médula ósea, definida por:
    -Recuento absoluto de neutrófilos (RAN) >= 1500/mm3 (1,5 x 109/l).
    -Plaquetas >= 100 000/mm3 (≥100 x 109/l).
    -Hemoglobina >= 9 g/dl.
    10.Función adecuada de la coagulación sanguínea definida por un cociente internacional normalizado (INR) <= 1,5 (excepto en los sujetos tratados con warfarina, en los que el INR debe ser <= 3,0 antes de la aleatorización).
    11.Función hepática adecuada, definida por:
    -Bilirrubina total <= 1,5 veces el LSN salvo para la hiperbilirrubinemia no conjugada del síndrome de Gilbert.
    -Fosfatasa alcalina (FA), alanina-aminotransferasa (ALT) y aspartato-aminotransferasa (AST) <= 3 x LSN (<= 5 × LSN en caso de metástasis hepáticas). Podrá incluirse a los sujetos con metástasis óseas con valores de FA superiores a 3 veces el LSN.
    12.El sujeto debe otorgar voluntariamente su consentimiento informado por escrito.
    13.El sujeto debe tener voluntad y capacidad para cumplir todos los aspectos del protocolo.
    E.4Principal exclusion criteria
    1. More than 1 prior VEGF-targeted treatment for advanced RCC.
    2. Subjects with Central Nervous System (CNS) metastases are not eligible, unless they have completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined as ≤10 mg prednisolone equivalent) before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
    3. Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months.
    4. Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days, or any investigational agent within 30 days prior to the first dose of study drug; subjects should have recovered from any toxicity related to previous anti-cancer treatment to CTC grade 0 or 1.
    5. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start.
    6. Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the excipients.
    7. Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible.
    8. Fasting total cholesterol > 300 mg/dL (or > 7.75 mmol/L) and/or fasting triglycerides level > 2.5 x ULN. NOTE: these subjects can be included after initiation or adjustment of lipid-lowering medication.
    9. Uncontrolled diabetes as defined by fasting glucose > 1.5 times the ULN. NOTE: these subjects can be included after initiation or adjustment of glucose-lowering medication.
    10. Prolongation of QTc interval to >480 ms.
    11. Subjects who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
    12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib or everolimus.
    13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
    14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
    15. Significant cardiovascular impairment within 6 months prior to the first dose of study drug; history of congestive heart failure greater than New York Heart Association (NYHA) Class II,unstable angina, myocardial infarction or stroke, cardiac arrhythmia associated with significant cardiovascular impairment or Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by screening multigated acquisition (MUGA) scan or echocardiogram.
    16. Active infection (any infection requiring systemic treatment).
    17.Any medical or other condition that in the opinion of the investigator(s) would preclude the subject’s participation in a clinical study.
    18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]). 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.
    19. Females of childbearing potential* who:
    do not agree to use a highly effective method of contraception for the entire study period and for 8 weeks after study drug discontinuation, ie:
    - total abstinence (if it is their preferred and usual lifestyle)
    - an intrauterine device (IUD) or hormone releasing system (IUS)
    - a contraceptive implant
    - an oral contraceptive** (with additional barrier method)
    OR
    do not have a vasectomized partner with confirmed azoospermia.
    For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable
    method of contraception, ie double barrier methods of contraception, such as condom plus diaphragm or cervical/vault cap with spermicide.
    1.Más de un tratamiento previo dirigido al VEGF por CCR avanzado.
    2.Los sujetos con metástasis del SNC no son elegibles, a menos que hayan completado un tratamiento local durante un mínimo de 4 sem. y hayan suspendido el uso de corticosteroides para esta indicación o no estén recibiendo un régimen de reducción progresiva de corticosteroides (definido como <=10 mg de un equivalente de prednisolona) antes de comenzar el tratamiento en este estudio. Cualquier signo (ej. radiológico) o síntoma de metástasis cerebrales debe permanecer estable durante al menos 4 sem. antes de comenzar el tto. del estudio.
    3.Cáncer activo (excepto CCR o carcinoma basocelular o epidermoide de la piel o carcinoma cervicouterino o de vejiga in situ tratados definitivamente) en los últimos 24 meses.
    4.Cualquier tratamiento antineoplásico (excepto radioterapia, véase el criterio de exclusión 5) en los 21 días anteriores ni ningún fármaco en investigación en los 30 días anteriores a la primera dosis de fármaco del estudio; los sujetos deben haberse recuperado de cualquier toxicidad relacionada con el tto. antineoplásico previo a grado 0 o 1 de los CTC.
    5.Radioterapia anterior en los 21 días previos al inicio del tto. del estudio, con la excepción de la radioterapia paliativa para las lesiones óseas, que está permitida si se completa 2 sem. antes del comienzo del tratamiento del estudio.
    6.Intolerancia conocida al fármaco del estudio (o cualquiera de sus excipientes) y/o hipersensibilidad conocida a las rapamicinas (ej. sirolimus, everolimus, temsirolimus) o cualquiera de sus excipientes.
    7.A los sujetos con proteinuria >1+ en el análisis de orina se les recogerá una muestra de orina de 24 horas para la valoración cuantitativa de la proteinuria. Los sujetos con proteinuria >=1 g/24 horas no podrán participar.
    8.Colesterol total en ayunas >300 mg/dl (o >7,75 mmol/l) o concentración de triglicéridos en ayunas > 2,5 x LSN. NOTA: estos sujetos podrán ser incluidos tras el inicio o el ajuste de la medicación hipolipemiante.
    9.Diabetes no controlada, definida por una glucosa en ayunas >1,5 veces el LSN. NOTA: estos sujetos podrán ser incluidos tras el inicio o el ajuste de la medicación hipoglucemiante.
    10.Prolongación del intervalo QTc a >480 ms.
    11.Sujetos que no se hayan recuperado correctamente de cualquier toxicidad o complicación derivada de una cirugía mayor antes del inicio del tto.
    12.Malabsorción digestiva, anastomosis del aparato digestivo o cualquier otro proceso que pueda afectar a la absorción de lenvatinib o everolimus.
    13.Trastornos hemorrágicos o trombóticos o sujetos con riesgo de hemorragia grave. Debe valorarse el grado de invasión/infiltración tumoral por parte de vasos sanguíneos importantes (ej. arteria carótida) por el riego potencial de hemorragia grave asociado a la reducción/necrosis del tumor después del tto. con lenvatinib.
    14.Hemoptisis clínicamente significativa o hemorragia tumoral en las 2 semanas previas a la primera dosis de fármaco del estudio
    15.Insuficiencia cardiovascular significativa en los 6 meses anteriores a la primera dosis del fármaco del estudio; antecedentes de insuficiencia cardiaca congestiva superior a la clase II de la NYHA, angina inestable, infarto de miocardio o derrame cerebral o arritmia cardíaca asociada a insuficiencia cardiovascular significativa, o FEVI por debajo del rango normal del centro de acuerdo con la determinación MUGA o ecocardiograma de selección.
    16.Infección activa (cualquier infección que exija tratamiento sistémico).
    17.Cualquier trastorno médico o de otro tipo que, en opinión del investigador impida la participación del sujeto en un ensayo clínico.
    18.Mujeres en período de lactancia o embarazadas (documentado mediante una determinación positiva de subunidad beta de la gonadotropina coriónica humana [β-hCG] o de gonadotropina coriónica humana [hCG]) con una sensibilidad mínima de 25 UI/l o unidades equivalentes de β-hCG [o hCG]) en las visitas de selección o basal). Se hará otra evaluación basal en caso de que la prueba de embarazo negativa de selección se haya obtenido más de 72 h. antes de administrar la primera dosis del fármaco del estudio.
    19.Mujeres con capacidad reproductiva que: no se comprometan a utilizar un método anticonceptivo muy eficaz durante todo el periodo del estudio y las 8 sem. posteriores a la suspensión del fármaco del estudio, es decir: abstinencia total (si se trata de su estilo de vida preferido y habitual), DIU o sistema SIU; implante anticonceptivo, anticonceptivos orales (con un método de barrera adicional) O cuya pareja no se haya sometido a una vasectomía y tenga azoospermia confirmada.
    En los centros de fuera de la Unión Europea se permite que en caso de que un método anticonceptivo muy eficaz no sea adecuado o aceptable para la paciente, esta se comprometa a utilizar un método anticonceptivo médicamente aceptable, es decir, métodos de doble barrera, como preservativo más diafragma o capuchón cervical con espermicida.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate at Week 24 (ORR24W) as assessed by the investigator according to RECIST 1.1 . ORR24W is defined as the proportion of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) at the Week-24 (after randomization) time point or earlier. To be considered a BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.
    Proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after randomization (as of the Week-24 time point).
    Tasa de respuesta objetiva (TRO) en la semana 24 (TRO24S) evaluada por el investigador conforme a los criterios RECIST 1.1. La TRO24S se define como la proporción de sujetos con la mejor respuesta global (MRG) de respuesta completa (RC) o respuesta parcial (RP) en el punto temporal de la semana 24 (después de la aleatorización) o antes. Para que se considere una MRG, todas las respuestas deben confirmarse no menos de 4 semanas después de la evaluación inicial de la respuesta.
    Porcentaje de sujetos con AAAT de grado 2 intolerables y cualquiera de grado >= 3 en las 24 semanas posteriores a la aleatorización (en el punto temporal de la semana 24).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Objective response rate (ORR24W) will be assessed at week-24 (after randomization) time point or earlier and at interim and final analysis.
    The safety end point for the primary analyses will be assessed within 24 weeks after randomisation.
    La Tasa de respuesta objetiva (TRO24S) se evaluara en la semana 24 (tras la aleatorización) o antes, y en el análisis intermedio y en el análisis final.
    El Criterio de valoración para los análisis primarios se evaluarán en las 24 semanas tras la aleatrorización.
    E.5.2Secondary end point(s)
    Progression-free survival (PFS), defined as the time from the date of randomization to the date of first documentation of disease progression or date of death, whichever occurs first. PFS censoring rules will be defined in the statistical analysis plan (SAP) .
    ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment.
    ORR is defined as the proportion of subjects with BOR of CR or PR at the end of treatment. To be considered BOR, all responses must be confirmed no less than 4 weeks after the initial assessment of response.
    Overall safety profile and tolerability of lenvatinib in combination with everolimus.
    Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion of subjects who discontinue study treatment due to TEAEs.
    Time to treatment failure due to toxicity, defined as the time from the date of randomization to the date that a subject discontinues study treatment due to TEAEs.
    Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.
    Overall survival (OS), measured from the date of randomization until date of death from any cause. In the absence of confirmation of death, subjects will be censored either at the date that the subject was last known to be alive or the date of data cutoff, whichever
    comes earlier.
    Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of Life (EuroQol) EQ-5D-3L instruments.
    PFS2, defined as the time from randomization to the date of disease progression after next line of therapy or death from any cause, whichever occurs first. PFS2 censoring rules will be defined in the SAP
    •Supervivencia libre de progresión (SLP), definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la primera documentación de progresión de la enfermedad o la fecha de fallecimiento, lo que suceda en primer lugar. Las reglas de censura de la SLP se definirán en el plan de análisis estadístico (PAE) y seguirán las directrices de la FDA.
    •TRO evaluada por el investigador conforme a los criterios RECIST 1.1 al final del tratamiento. La TRO se define como la proporción de sujetos con MRG de RC o RP al final del tratamiento. Para que se considere una MRG, todas las respuestas deben confirmarse no menos de 4 semanas después de la evaluación inicial de la respuesta.
    •Perfil global de seguridad y tolerabilidad de lenvatinib en combinación con everolimus.
    •Porcentaje de sujetos que dejan de tomar el tratamiento por toxicidad, lo que se define como el porcentaje de sujetos que interrumpe el tratamiento del estudio por AAAT.
    •Tiempo hasta el fracaso del tratamiento por toxicidad, definido como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha en la que el sujeto suspende el tratamiento del estudio debido a AAAT.
    •Parámetros de la exposición a lenvatinib y everolimus e interacciones farmacológicas FC y FD.
    •Supervivencia global (SG), determinada desde la fecha de aleatorización hasta la fecha de la muerte por cualquier causa. En ausencia de confirmación del fallecimiento, se censurará a los sujetos en la fecha en que se supo por última vez que estaban vivos o en la fecha de corte de los datos, lo que ocurra antes.
    •La calidad de vida relacionada con la salud (CdVRS) se evaluará mediante los instrumentos siguientes: la Evaluación funcional de la terapia contra el cáncer - índice de síntomas renales - síntomas relacionados con la enfermedad (FKSI-DRS), el cuestionario QLQ-C30 de la Organización europea para la investigación y el tratamiento del cáncer (EORTC) y el cuestionario EQ-5D-3L del Grupo europeo de calidad de vida (EuroQol).
    •SLP2, definida como el tiempo transcurrido desde el momento de la aleatorización hasta la fecha de la progresión de la enfermedad tras la siguiente línea de tratamiento o la muerte por cualquier causa, lo que ocurra antes. Las normas de censura de la SLP2 se definirán en el PAE.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The median survival time and the survival rates at 12 , 18 and 24 months will be assessed.
    HRQoL will be assessed at Baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle, at time of early withdrawal, and at the Off-Treatment Visit.
    Se evaluará la mediana del tiempo de supervivencia y las tasas de supervivencia a los 12, 18 y 24 meses.
    El HRQoL se evaluará en el momento basal (antes de la administración d ela primera dosis del fármaco del estudio), el día 1 de cada ciclo subsiguiente, en la retirada prematura y en la visita de fin de tratamiento.
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA55
    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
    Bulgaria
    Canada
    Czech Republic
    Finland
    Greece
    Korea, Republic of
    Netherlands
    Poland
    Portugal
    Romania
    Russian Federation
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    UVUP
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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: 136
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 170
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 306
    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)
    At the completion of the Randomization Phase, subjects still receiving study treatment may continue taking lenvatinib and everolimus available through their pharmacy (if commercially available for that individual subject) or through an access program administered by the sponsor.
    Al completar la fase de aleatorización, los sujetos que aun estén en tratamiento con lenvatinib podrán seguir el tratamiento con lenvatinib y everolimus a través de su farmacia (si están comercializados para dicho sujeto) o a través del programa de accesibilidad gestionado por el promotor.
    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 Decision2017-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-23
    P. End of Trial
    P.End of Trial StatusOngoing
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