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    Summary
    EudraCT Number:2014-002230-32
    Sponsor's Protocol Code Number:WO29479
    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:2014-10-20
    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 number2014-002230-32
    A.3Full title of the trial
    A MULTISTAGE, PHASE II, STUDY EVALUATING THE SAFETY AND EFFICACY OF COBIMETINIB IN COMBINATION WITH PACLITAXEL AS FIRST-LINE TREATMENT FOR PATIENTS WITH METASTATIC TRIPLE-NEGATIVE BREAST CANCER
    ESTUDIO DE FASE II, MULTIFÁSICO, PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE COBIMETINIB EN COMBINACIÓN CON PACLITAXEL COMO TRATAMIENTO DE PRIMERA LÍNEA EN PACIENTES CON CÁNCER DE MAMA TRIPLE NEGATIVO METASTÁSICO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multi-part, clinical study testing the safety and effectiveness of cobimetinib in combination with paclitaxel as initial treatment for patients with triple-negative (HER2 negative, Estrogen receptor negative, and Progesterone receptor negative) breast cancer that has spread.
    Estudio clínico multietapa, para evaluar la seguridad y la eficacia de cobimetinib en combinación con paclitaxel como terapia inicial para pacientes con cáncer de mama triple negativo (Her2 negativo, receptores de estrogeno y receptores de progesterona negativo) que se ha dispersado.
    A.4.1Sponsor's protocol code numberWO29479
    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 SponsorF. Hoffman-La Roche Ltd., realizado en España por Roche Farma S.A.
    B.1.3.4CountrySwitzerland
    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 supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+34 913257300
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 nameCobimetinib (GDC-0973)
    D.3.2Product code RO5514041/F04
    D.3.4Pharmaceutical form Film-coated 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 INNCobimetinib (GDC-0973)
    D.3.9.1CAS number 934660-93-2
    D.3.9.2Current sponsor codeRO5514041
    D.3.9.3Other descriptive nameCOBIMETINIB, GDC-0973/XL518
    D.3.9.4EV Substance CodeSUB122319
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC, Germany
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code Ro0247506 - 150mg/25ml
    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.3.9.2Current sponsor codeRo024-7506
    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 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 Yes
    D.3.11.13.1Other medicinal product type- taxane, obtained semisynthetically from a taxane precursor derived from the needles and twigs of the European yew, Taxus baccata.
    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 Paclitaxel
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC, Germany
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code Ro0247506 - 300mg/50ml
    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.3.9.2Current sponsor codeRo024-7506
    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 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 Yes
    D.3.11.13.1Other medicinal product type- taxane, obtained semisynthetically from a taxane precursor derived from the needles and twigs of the European yew, Taxus baccata.
    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 placeboFilm-coated tablet
    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
    Patients with metastatic or locally advanced, triple-negative adenocarcinoma of the breast that have not received prior systemic therapy for metastatic breast cancer.
    Pacientes con adenocarcinoma triple negativo mestastásico o localmente avanzado que no haya recibido tratamiento sistémico previo para el CMM.
    E.1.1.1Medical condition in easily understood language
    Patients with metastatic (cancer that has spread) or locally advanced (cancer that has regrown at or near the original site) triple-negative breast cancer that have not received treatment.
    Pacientes con cáncer de mama triple negativo metastásico(cáncer que se ha extendido)o localmente avanzado(cáncer que ha vuelto a crecer en o cerca del sitio original)que no hayan recibido tratamiento.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the clinical benefit of cobimetinib + paclitaxel relative to placebo + paclitaxel, as measured by investigator-assessed PFS in patients with locally advanced or metastatic TNBC.
    Determinar el beneficio clínico de cobimetinib + paclitaxel en comparación con placebo + paclitaxel, en función de la SSP evaluada por el investigador en pacientes con cáncer de mama triple negativo localmente avanzado o metastásico.
    E.2.2Secondary objectives of the trial
    -To evaluate the safety and tolerability of cobimetinib administered in combination with paclitaxel in patients with locally advanced or metastatic TNBC.
    -To determine the overall response rate (ORR) and duration of response of cobimetinib + paclitaxel and placebo + paclitaxel
    -To evaluate OS benefit of cobimetinib + paclitaxel and placebo + paclitaxel
    -To characterize the pharmacokinetics of cobimetinib administered in combination with paclitaxel
    - Evaluar la seguridad y la tolerabilidad de la administración de cobimetinib en combinación con paclitaxel en pacientes con cáncer de mama triple negativo localmente avanzado o metastásico.
    - Determinar la tasa de respuesta global (TRG) y la duración de la respuesta de cobimetinib + paclitaxel y de placebo + paclitaxel.
    - Evaluar el beneficio clínico sobre la supervivencia global (SG) de cobimetinib + paclitaxel y de placebo + paclitaxel.
    - Describir la farmacocinética de cobimetinib y paclitaxel cuando se administran en combinación
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ?Signed Informed Consent Form
    ?Women and men, age ? 18 years
    ?Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    ?Histologically confirmed ER negative, PR negative, and HER2-negative adenocarcinoma of the breast, with measurable metastatic or locally recurrent disease
    ?Locally recurrent disease must not be amenable to resection with curative intent.
    ?Measurable disease, according to RECIST, v1.1 (see Appendix 4)
    ?Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment:
    ?Absolute neutrophil count (ANC) ? 1.5 × 10 exp9/L
    ?Platelet count ? 100 × 10 exp9/L
    ?Hemoglobin ? 9 g/dL
    ?Albumin ? 2.5 g/dL
    ?Bilirubin ? 1.5 × the upper limit of normal (ULN)
    ?Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase ? 3 × ULN, with the following exceptions:
    -Patients with documented liver metastases: AST and/or ALT ? 5 × ULN
    -Patients with documented liver or bone metastases: alkaline phosphatase ? 5 × ULN
    ?Serum creatinine ? 1.5 × ULN or creatinine clearance (CrCl) ? 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or Cockroft-Gault glomerular filtration rate estimation:
    (140-age) x (weight in kg) x (0.85 if female)
    72 x (serum creatinine in mg/dL)
    ?Ability and capacity to comply with the study and follow-up procedure
    ?For female patients (and female partners of male patients) who are not postmenopausal (? 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study drug
    ? The determination of TNBC status should, whenever possible, utilize tissue from a metastatic or recurrent lesion and where more than one biopsy source is available, priority should be given to the most recent
    sample.
    ? Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible.
    - Documento de consentimiento informado firmado.
    - Varones y mujeres, con edad ? 18 años.
    - Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1.
    - Adenocarcinoma de mama con enfermedad metastásica mensurable o localmente recurrente, con confirmación histológica de negatividad para RE, RP y HER2.
    - La enfermedad localmente recurrente no debe ser susceptible de resección con intención curativa.
    - Enfermedad mensurable conforme a los criterios RECIST, v1.1 (véase el Apéndice 4)
    - Función hematológica y orgánica adecuada, definida por los siguientes resultados analíticos obtenidos en los 14 días previos a la administración de la primera dosis del tratamiento con el fármaco de estudio:
    ? Recuento absoluto de neutrófilos (RAN) ? 1,5 x 109/l
    ? Recuento de plaquetas ? 100 x 109/l
    ? Hemoglobina ? 9 g/dl
    ? Albúmina ? 2,5 g/dl
    ? Bilirrubina ? 1,5 x Límite superior de normalidad (LSN)
    ? AST, ALT y fosfatasa alcalina ? 3 x LSN, con las siguientes excepciones:
    ? Pacientes con metástasis hepáticas documentadas: AST y/o ALT ? 5 x LSN.
    ? Pacientes con metástasis hepáticas u óseas documentadas: fosfatasa alcalina ? 5 x LSN
    ? Creatinina sérica ? 1,5 x LSN o aclaramiento de creatinina (CrCl) ? 40 ml/min en función del CrCl calculado en una muestra de orina de 24 horas o a partir de la estimación de la filtración glomerular mediante la fórmula de Cockcroft-Gault:
    (140 - edad) x (peso en kg) x (0,85 en mujeres)/72 x (creatinina sérica en mg/dl)
    - Aptitud y capacidad para cumplir los procedimientos del estudio y del seguimiento.
    - Las pacientes que sean mujeres (y las parejas de los pacientes varones), que no sean posmenopáusicas (amenorrea no inducida por tratamiento ?12 meses) o que no se hayan sometido a esterilización quirúrgica (ausencia de ovarios o útero), deberán comprometerse a no mantener relaciones sexuales o a utilizar uno o varios métodos anticonceptivos con una tasa de fracaso de < 1 % al año durante el período de tratamiento y durante al menos 6 meses después de la última dosis del fármaco del estudio.
    - Para la determinación del estado del CMTN se usará siempre que sea posible tejido de una lesión recidivante o metastásica y, cuando se disponga de más de una biopsia, se dará prioridad a la muestra más
    reciente.
    - No podrán participar las pacientes que no se hayan sometido a análisis de HER2, RE o RP y, por tanto, se desconozca el estado de HER2, RE y RP del adenocarcinoma de mama.
    E.4Principal exclusion criteria
    ?Known HER2 positive, ER positive, or PR positive breast cancer by local laboratory assessment (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Medical Monitor to establish eligibility of the patient).
    ?HER2 positivity is defined as one of the following: IHC 3 positive or in situ hybridization (ISH) positive
    ?ER and PR positivity is defined positive for ER or PR if a ?nding of ?1% of tumor cell nuclei are immunoreactive
    ?Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible.
    ?Any prior chemotherapy, hormonal, or targeted therapy, for inoperable locally advanced or mTNBC
    ?Prior chemotherapy (including taxanes) and/or radiation in the neoadjuvant or adjuvant setting is allowable if treatment occurred ? 6 mos prior to initiation of study treatment (Cycle 1 Day1)
    ?Any systemic anti-cancer therapy within 3 weeks prior to Cycle 1, Day 1
    ?Any radiation treatment to metastatic site within 28 days of Cycle 1, Day 1
    ?Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to Cycle 1, Day 1, or anticipation of need for major surgical procedure during the course of the study
    ?Prior therapy with bevacizumab, sorafenib, sunitinib, or other putative vascular endothelial growth factor pathway?targeted therapy following diagnosis of breast cancer
    ?Prior exposure to experimental treatment targeting Raf, MEK, or the MAPK pathway
    ?Previous therapy with Akt, PI3K, and/or mTOR inhibitors
    ?Prior therapy with trastuzumab
    ?Grade ? 2 peripheral neuropathy
    ?Brain metastases (symptomatic or non-symptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g. radiation,surgery or steroids) to control symptoms from brain metastases within 60 days prior to first study treatment dose
    ?History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
    ?Patients will be excluded if they currently have the following risk factors for RVO:
    -Uncontrolled glaucoma with intra-ocular pressures ? 21mmHg
    -Serum cholesterol ? Grade 2
    -Hypertriglyceridemia ? Grade 2
    -Hyperglycemia (fasting) ? Grade 2
    -Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower.
    -The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
    -St. John?s wort or hyperforin (potent CYP3A4 enzyme inducer)
    -Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
    -Pregnancy (positive serum pregnancy test) or lactation
    -Uncontrolled serious medical or psychiatric illness
    -Active infection requiring intravenous (IV) antibiotics on Cycle 1 Day 1
    ?QTc interval at screening > 480 msec (average of triplicate screening measurements)
    ?Patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil)
    - Cáncer de mama HER2+, RE+ o RP+ conocido mediante evaluación del laboratorio local (si se dispone de varios resultados analíticos y alguno de ellos no cumple la definición de los criterios de elegibilidad del CMTN, deberán comentarse todos los resultados con el monitor médico para determinar la elegibilidad del paciente).
    ? La positividad para HER2 se define como una de las siguientes: IHQ triple positiva o hibridación in situ (ISH) positiva.
    ? La positividad para RE y RP se define como el hallazgo de que ? 1 % de los núcleos celulares del tumor son inmunoreactivos.
    - No podrán participar las pacientes que no se hayan sometido a análisis de HER2, RE o RP y, por tanto, se desconozca el estado de HER2, RE y RP del adenocarcinoma de mama.
    - Quimioterapia, tratamiento hormonal o tratamientos específicos para el CMTN localmente avanzado irresecable o metastásico.
    Se permite la quimioterapia (con taxanos) o la radioterapia neoadyuvante o adyuvante previa si el tratamiento se ha administrado ? 6 meses antes del
    inicio del tratamiento del estudio (día 1 del ciclo 1).
    - Cualquier tratamiento antineoplásico sistémico en las 3 semanas previas al día 1 del ciclo 1.
    - Radioterapia de un foco metastásico en los 28 días anteriores al día 1 del ciclo 1.
    - Intervención de cirugía mayor, biopsia abierta o traumatismo importante en los 30 días previos al día 1 del ciclo 1 o previsión de la necesidad de una intervención de cirugía mayor durante el estudio.
    - Tratamiento previo con bevacizumab, sorafenib, sunitinib u otros posibles tratamientos dirigidos a la vía del factor de crecimiento del endotelio vascular
    posteriores al diagnóstico de cáncer de mama.
    - Exposición previa a tratamientos experimentales dirigidos a la vía de RAF, MEK o MAPK.
    - Tratamiento previo con inhibidores de Akt, PI3K o mTOR.
    - Tratamiento previo con trastuzumab.
    - Neuropatía periférica de grado ? 2.
    - Metástasis cerebrales (sintomáticas o asintomáticas) sin tratamiento previo, progresivas o que precisan cualquier tipo de tratamiento (p. ej., radioterapia, cirugía o esteroides) para el control de los síntomas en los 60 días previos a administración de la primera dosis del tratamiento del estudio.
    - Antecedentes o indicios de patologías de la retina diagnosticas mediante examen oftalmológico que se consideren un factor de riesgo del desprendimiento de la retina neurosensorial/coriorretinopatía serosa central (CSC), la oclusión de las venas retinianas (OVR) o la degeneración macular neovascular.
    - Se excluirá del estudio a los pacientes que presenten en la actualidad los siguientes factores de riesgo de OVR:
    ? Glaucoma no controlado con presiones intraoculares ? 21mmHg
    ? Colesterol sérico ? grado 2
    ? Hipertrigliceridemia ? grado 2
    ? Hiperglucemia (en ayunas) ? grado 2
    - Fracción de eyección del ventrículo izquierdo (FEVI) por debajo del límite inferior de la normalidad (LIN) del centro o inferior al 50 %, lo que sea inferior.
    - Se prohíbe la ingesta de los siguientes alimentos/suplementos durante el tratamiento y al menos los 7 días previos al inicio del mismo:
    ? Hipérico o hiperforina (inductores potentes de la enzima CYP3A4).
    ? Zumo de pomelo (inhibidor potente de la enzima CYP3A4 del citocromo P450).
    - Embarazo (prueba de embarazo en suero positiva) o lactancia.
    - Enfermedad médica o psiquiátrica grave no controlada.
    - Infección activa que requiere tratamiento antibiótico por vía intravenosa (i.v.) el día 1 del ciclo 1.
    - Intervalo QTc en la selección > 480 ms (promedio de tres mediciones de la selección).
    - Pacientes con antecedentes de reacciones de hipersensibilidad a paclitaxel u otros fármacos que contengan la formulación de Cremophor ® EL (polioxietilenados de aceite de ricino).
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by investigator per RECIST v1.1, or death on study from any cause, whichever occurs first.
    El criterio de valoración principal de la eficacia es la Supervivencia sin progresión (SSP), definida como el tiempo transcurrido entre la aleatorización y el primer episodio de progresión de la enfermedad, determinada por el investigador conforme a los criterios RECIST, o la muerte por cualquier causa, lo que antes suceda.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The PFS analysis will be performed after approximately 60 investigator-assessed PFS events (estimated to be approximately 21 months after the first patient is enrolled).
    El análisis de la SSP se completará tras aproximadamente 60 acontecimientos de progresión determinada por el investigador (lo que se espera que suceda aproximadamente 21 meses después de la inclusión del primer paciente)
    E.5.2Secondary end point(s)
    Overall survival, defined as the time from randomization to death from any cause, regardless of whether the death occurs during the study or following treatment discontinuation. For patients who have not died, OS will be censored at the date of last contact. OS will be analyzed similarly to the primary endpoint.
    SG, definida como el tiempo transcurrido entre la aleatorización y la muerte por cualquier causa, con independencia de si la muerte se produce durante el estudio o después de la retirada del tratamiento. En los pacientes que no fallezcan, la SG se censurará a fecha del último contacto. La SG se analizará de modo similar al criterio de valoración principal.
    E.5.2.1Timepoint(s) of evaluation of this end point
    To be done at time of primary analysis
    A realizarse en el momento del análisis principal.
    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 Yes
    E.8.1.7.1Other trial design description
    Comienza con una etapa de seguridad abierta previa a randomización.Expansion controla con placebo.
    study start with an open label safety run in stage prior to a random. placebo controlled expansion.
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA29
    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
    Belgium
    Czech Republic
    France
    Korea, Republic of
    Spain
    Taiwan
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    UVUP (última visita del último paciente)
    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 months1
    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 months1
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 58
    F.4.2.2In the whole clinical trial 112
    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)
    Once patients have ended participation in the trial they will be free to pursue other available treatments or may participate in other clinical trials as advised by their treating physician. Patients in the control/placebo arm of the expansion stage will not be allowed access to cobimetinib.
    Una vez finalizada su participación en el ensayo, los pacientes podrán optar libremente a otros tratamientos disponibles o participar en otros ensayos clínicos de acuerdo a lo aconsejado por su médico. Los pacientes del brazo control/placebo de la fase de ampliación no tendrán permitido el acceso a cobimetinib.
    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 Decision2014-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-09
    P. End of Trial
    P.End of Trial StatusOngoing
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