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    Summary
    EudraCT Number:2014-003032-39
    Sponsor's Protocol Code Number:CLEE011X2110C
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-20
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-003032-39
    A.3Full title of the trial
    A phase Ib/II study of the ALK inhibitor ceritinib in combination with the CDK4/6 inhibitor LEE011 in patients with ALK-positive Non-small Cell Lung Cancer
    Estudio de fase Ib/II de ceritinib inhibidor de ALK en combinación con LEE011 inhibidor de CDK4/6 en pacientes con cáncer de pulmón de células no pequeñas ALK-positivo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase Ib/II study of certinib in combination with LEE011 in patients with ALK-positive Non-Small Cell Lung Cancer
    Estudio de seguridad y eficacia de LEE011 y ceritinib en pacientes con cáncer de pulmón de células no pequeñas ALK-positivo
    A.4.1Sponsor's protocol code numberCLEE011X2110C
    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 SponsorNovartis Farmacéutica, S.A.
    B.1.3.4CountrySpain
    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 supportNovartis Pharma Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A.
    B.5.2Functional name of contact pointDepartamento Médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34900353036
    B.5.5Fax number34932479903
    B.5.6E-maileecc.novartis@novartis.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 nameLEE011 50 mg
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Capsule
    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 INNLEE011
    D.3.9.1CAS number LEE011
    D.3.9.2Current sponsor codeLEE011
    D.3.9.3Other descriptive nameLEE011
    D.3.9.4EV Substance CodeSUB31644
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 nameLEE011 200 mg
    D.3.2Product code LEE011
    D.3.4Pharmaceutical form Capsule
    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 INNLEE011
    D.3.9.1CAS number LEE011
    D.3.9.2Current sponsor codeLEE011
    D.3.9.3Other descriptive nameLEE011
    D.3.9.4EV Substance CodeSUB31644
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 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 nameLDK378 50 mg
    D.3.2Product code LDK378
    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 INNceritinib
    D.3.9.1CAS number LDK378
    D.3.9.2Current sponsor codeLDK378
    D.3.9.3Other descriptive nameLDK378
    D.3.9.4EV Substance CodeSUB130802
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 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 nameLDK378 150 mg
    D.3.2Product code LDK378
    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 INNceritinib
    D.3.9.1CAS number LDK378
    D.3.9.2Current sponsor codeLDK378
    D.3.9.3Other descriptive nameLDK378
    D.3.9.4EV Substance CodeSUB130802
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Non-Small Cell Lung Cancer
    Cáncer de pulmón de células no pequeñas ALK-positivo.
    E.1.1.1Medical condition in easily understood language
    Lung cancer
    Cáncer de pulmón
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung 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
    ?Phase Ib: To estimate the MTD(s) and/or RP2D(s) of LEE011 in combination with ceritinib in ALK-positive NSCLC patients as measured by the incidence of DLTs in Cycle 1 and by exposure to LEE011 and ceritinib as measured by PK parameters
    ?Phase II: To assess preliminary anti-tumor activity of the LEE011 and ceritinib combination as measured by Overall Response Rate (ORR) as per RECIST v1.1
    1: Estimar la(s) MTD(s) y/o RP2D(s) de LEE011 en combinación con ceritinib en pacientes con NSCLCL ALK-positivo medido por la incidencia de DLTs en el Ciclo 1 y por la exposición a LEE011 y ceritinib medido por los parámetros de PK
    2: Evaluar la actividad anti-tumoral preliminar de la combinación de LEE011 y ceritinib medida por la Tasa de Respuesta Global (ORR) según RECIST v1.1
    E.2.2Secondary objectives of the trial
    ?To characterize the safety and tolerability of the LEE011 and ceritinib combination as measured by the frequency and severity of adverse events and serious adverse events, changes in laboratory values, and electrocardiograms, and by the frequency of dose interruptions and dose reductions.
    ?To characterize the PK profile of LEE011 and ceritinib combination as measured by concentration-time profiles and derived PK parameters.
    ?To assess additional clinical activity of the LEE011 and ceritinib combination as measured by Progression free survival, duration of response, time to response, disease Control Rate, and overall survival.
    1: Caracterizar la seguridad y tolerabilidad de la combinación de LEE011 y ceritinib medido por la frecuencia y severidad de los acontecimientos adversos, acontecimientos adversos graves, cambios en los valores de laboratorio, y electrocardiogramas, y por la frecuencia de interrupciones de dosis y reducciones de dosis.
    2: Caracterizar el perfil de PK de la combinación LEE011 y ceritinib medido por los perfiles concentración-tiempo y los parámetros de PK obtenidos.
    3: Evaluar la actividad clínica adicional de la combinación de LEE011 y ceritinib medido por la supervivencia libre de progresión, duración de respuesta, tiempo hasta la respuesta, tasa de control de la enfermedad, y supervivencia global.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ?Male or female aged greater than or equal to 18 years
    ?Patients must be diagnosed with ALK-positive advanced NSCLC. The tumor must be ALK-positive as determined by ALK rearrangement in greater than or equal to15% of cells (as measured by FISH using the Vysis break-apart ALK probe) or by using the Ventana ALK IHC test. The analysis may be performed locally.
    ?Eastern cooperative oncology group (ECOG) performance status ? 2.
    ?Measurable disease as per RECIST v1.1
    ?Availability of tumor sample:
    oFor ALK inhibitor naïve patients:
    A representative tumor sample must be submitted. An archival tumor specimen is acceptable
    oFor patients after progression on an ALK inhibitor:
    A new tumor biopsy is required unless a biopsy performed after progression on the patient?s most recent ALK inhibitor is available for submission
    oFor all patients a newly obtained tumor specimen must be submitted if no appropriate archival sample is available. In the event that no sample is available and a new biopsy cannot be obtained, enrollment may be considered after discussion with the sponsor.
    Hombre o mujer de 18 años de edad o mayores.
    Enfermedad medible según RECIST 1.1.
    Estado de actividad ECOG 0-2.
    Los pacientes deben estar diagnosticados de NSCLC avanzado ALK-positivo. El tumor debe ser ALK-positivo determinado por reordenamiento de ALK en mayor o igual a 15% de las células (medido mediante FISH utilizando la sonda de ALK break-apart de Vysis) o utilizando la prueba Ventana ALK IHC. El análisis se puede realizar localmente.
    E.4Principal exclusion criteria
    ?For dose escalation part:
    oPatients who have received prior treatment with ceritinib cannot be enrolled in the escalation part of the study until a combination drug dose with appropriate ceritinib exposure is determined. Prior therapy with other ALK inhibitors is allowed.
    ?For Phase II part:
    oGroup A: prior therapy with any ALK inhibitor is not permitted.
    oGroup B: progression following any ALK inhibitor(s) other than ceritinib is required and the last dose of the ALK inhibitor must be no more than 60 days prior to the first dose of study drug. Prior ceritinib is not permitted.
    oGroup C: progression following ceritinib is required and the last dose of ceritinib must be no more than 60 days prior to the first dose of study drug. Patients must have tolerated a dose of ceritinib of 600 mg QD, or greater.
    ?Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS disease
    ?Impaired cardiac function or any clinically significant cardiac disease, including any of the following:
    oClinically significant heart disease such as CHF requiring treatment (NYH grade greater than or equal to 2), unstable angina pectoris or myocardial infarction within the past 3 months, or left ventricular ejection fraction (LVEF) < 45% or less than the institution lower limit of normal as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
    oQT corrected with Fridericia?s (QTcF) >450 ms screening ECG or congenital long QT syndrome or family history of unexpected sudden cardiac death.
    oAny other clinically significant heart disease such as unstable arrhythmia, resting bradycardia, left bundle branch block, bifascicular block, or any heart disease that requires the use of a cardiac pacemaker ? 3 months prior to starting study drug
    ?Patients with the following laboratory values during screening and on day 1 of pre-dose:
    oHematology
    -Absolute neutrophil count (ANC) < 1.5 x 109/L
    -Platelet count < 100 x 109/L
    -Hemoglobin (Hgb) < 9 g/dL
    oBiochemistry
    -Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
    -Total bilirubin > 1.5 x ULN, except for patients with known Gilbert syndrome, who are excluded if total bilirubin is > 3.0 x ULN or direct bilirubin is > 1.5 x ULN
    -Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor involvement of the liver, who must have a value ? 5 x ULN
    -Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor involvement of the liver, who must have a value ? 5 x ULN
    -Potassium, magnesium or calcium abnormality > CTCAE grade 1 (despite oral supplementation)
    -Phosphate abnormality > CTCAE grade 2 (despite oral supplementation)
    ?Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ceritinib or LEE011 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
    ?Patients who are currently receiving treatment (that cannot be discontinued at least 1 week prior to the initiation of the study) with agents that are known to be any of the following:
    oStrong inducers or inhibitors of CYP3A4/5
    oPrimarily metabolized by CYP3A4/5 or CYP2C9
    oSubstrates of CYP3A4/5 or CYP2C9 with a narrow therapeutic index
    Para la parte de escalado de dosis:
    Los pacientes que hayan recibido tratamiento previo con ceritinib no pueden ser incluidos en la parte de escalado del estudio hasta que se determine una dosis de la combinación de fármacos con adecuada exposición a ceritinib (ver la Sección 6.2.1). La terapia previa con otros inhibidores de ALK está permitida.
    Para la parte de la Fase II:
    Grupo A: no está permitida la terapia previa con ningún inhibidor de ALK.
    Grupo B: es necesaria la progresión después de cualquier inhibidor(es) de ALK aparte de ceritinib y la última dosis del inhibidor de ALK debe ser no más de 60 días antes de la primera dosis del fármaco del estudio. No está permitido ceritinib previo.
    Grupo C: es necesaria la progresión después de ceritinib y la última dosis de ceritinib debe ser no más de 60 días antes de la primera dosis del fármaco del estudio. Los pacientes deben haber tolerado una dosis de ceritinib de 600 mg QD, o superior.
    Grupos B2 y C2: si el resultado del análisis intermedio es negativo, los pacientes con estado G1202R conocido en la selección se excluirán del estudio.
    Pacientes con metástasis sintomáticas del sistema nervioso central (SNC) que son neurológicamente inestables o precisan aumentos de dosis de esteroides o terapia local dirigida al SNC (como radioterapia, cirugía o quimioterapia intratecal) para controlar su enfermedad del SNC.
    Función cardiaca alterada o cualquier enfermedad cardiaca clínicamente significativa, incluyendo alguna de las siguientes:
    Enfermedad cardiaca clínicamente significativa como CHF que precisa tratamiento (grado NYH mayor o igual a 2), angina pectoris inestable o infarto de miocardio en los últimos 3 meses anteriores, o fracción de eyección ventricular izquierda (FEVI) < 45% o menos que el límite inferior de normalidad de la institución determinado mediante imagen por ventriculografía isotópica (MUGA) o ecocardiograma (ECO).
    ECG de la selección con QT corregido con Fridericia (QTcF) > 450 mseg o síndrome QT largo congénito o historia familiar de muerte cardiaca súbita inesperada.
    Cualquier otra enfermedad cardiaca clínicamente significativa como arritmia inestable, bradicardia en reposo, bloqueo de rama izquierda, bloqueo bifascicular, o cualquier enfermedad cardiaca que precise el uso de marcapasos cardiaco ? 3 meses antes del inicio del fármaco del estudio
    Pacientes con los siguientes valores de laboratorio durante la selección y en el día 1 de pre-dosis:
    Hematología (la transfusión antes del inicio del estudio para alcanzar los criterios de inclusión no es aceptable)
    Recuento absoluto de neutrófilos (ANC) < 1,5 x 109/L
    Recuento de plaquetas < 100 x 109/L
    Hemoglobina (Hgb) < 9 g/dL
    Bioquímica
    Aclaramiento de creatinina (calculado utilizando la fórmula de Cockcroft-Gault, o medido) < 50 mL/min
    Bilirrubina total > 1,5 x LSN, excepto para pacientes con síndrome de Gilbert conocido, que son excluidos si la bilirrubina total es > 3,0 x LSN o la bilirrubina directa es > 1,5 x LSN
    Alanino aminotransferasa (ALT) > 3 x LSN, excepto para pacientes que tienen afectación tumoral del hígado, que deben tener un valor ? 5 x LSN
    Aspartato aminotransferasa (AST) > 3 x LSN, excepto para pacientes que tienen tumoral del hígado, que debe tener un valor ? 5 x LSN
    Anomalía de potasio, magnesio o calcio > grado 1 CTCAE (a pesar de suplemento oral)
    Anomalía de fosfato > grado 2 CTCAE ( a pesar de suplemento oral)
    Alteración de la función gastrointestinal (GI) o enfermedad GI que puede alterar significativamente la absorción de ceritinib o LEE011 (p.e., enfermedades ulcerativas, náuseas no controladas, vómitos, diarrea, o síndrome de malabsorción)
    Pacientes que actualmente están recibiendo tratamiento (que no se pueden retirar al menos 1 semana antes del inicio del estudio) con agentes que se sabe que son uno de los siguientes:
    Inductores o inhibidores fuertes de CYP3A4/5
    Metabolizado principalmente por CYP3A4/5 o CYP2C9
    Sustratos de CYP3A4/5 o CYP2C9 con un estrecho índice terapéutico y medicaciones con un conocido riesgo de prolongación del intervalo QT o que inducen Torsades de Pointes.
    E.5 End points
    E.5.1Primary end point(s)
    Phase Ib:
    1.Incidence rate of DLTs during the first cycle of treatment
    2.Exposure to LEE011 and ceritinib as measured by PK parameters (AUC0-24h at C1D15)
    Phase II:
    3.Overall Response Rate (ORR) as per RECIST v1.1
    Fase Ib:
    1.Tasa de incidencia de DLTs durante el primer ciclo de tratamiento
    2.Exposición a LEE011 y ceritinib medido por los parámetros de PK (AUC0-24h en el C1D15)
    Fase II:
    3.Tasa de Respuesta Global (ORR) según RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. 28 days
    2. C1D15
    3. 30 months
    1. 28 días
    2. C1D15
    3. 30 meses
    E.5.2Secondary end point(s)
    Phase Ib:
    1.Overall Response Rate (ORR)

    Phase Ib + II:
    2.Progression free survival (PFS) per RECIST v1.1
    3.Duration of response (DOR)
    4.Time to response (TTR)
    5.Disease Control Rate (DCR)
    6.Overall survival (OS)

    7.Safety: Frequency and severity of adverse events and serious adverse events, changes in laboratory values, and electrocardiograms.
    8.Tolerability: Frequency of dose interruptions and dose reductions

    9.PK parameters of LEE011 and ceritinib
    Fase Ib:
    1.Tasa de Respuesta Global (ORR)
    Fase Ib + II:
    2.Supervivencia libre de progresión (PFS) según RECIST v1.1
    3.Duración de respuesta (DOR)
    4.Tiempo hasta la respuesta (TTR)
    5.Tasa de Control de la Enfermedad (DCR)
    6.Supervivencia Global (SG)
    7.Seguridad: Frecuencia y severidad de acontecimientos adversos y acontecimientos adversos graves, cambios en los valores de laboratorio, y electrocardiogramas
    8.Tolerabilidad: Frecuencia de interrupciones de dosis y reducciones de dosis
    9.Parámetros de PK de LEE011 y ceritinib
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. end of phase Ib
    2. to 9. 30 months
    1. Fin de la fase Ib
    2. hasta 9. 30 meses
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose escalation
    Escalada de dosis
    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 Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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 Yes
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Hong Kong
    Korea, Republic of
    Singapore
    Taiwan
    Thailand
    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
    NA
    NA
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 34
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 51
    F.4.2.2In the whole clinical trial 170
    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)
    All patients will have a 30 day follow up visit after the last dose of study treatment.
    Patients enrolled in the Phase II part of the study will be followed for survival every 3 months per phone call until death, or until the last patient has been followed for at least 12 months after the start of study treatment, or has been lost to follow-up or withdrew consent, whichever occurs first.
    Todos los pacientes deben tener evaluaciones de seguridad durante 30 días después de la última dosis del tratamiento del estudio. Los pacientes incluidos en la parte de expansión del estudio serán seguidos por supervivencia cada 3 meses mediante llamadas telefónicas hasta la muerte, o hasta que el último paciente haya sido seguido durante al menos 12 meses después del inicio del tratamiento del estudio, o haya sido pérdida de seguimiento o retirara el consentimiento, lo que suceda primero.
    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 Decision2014-12-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-26
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