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    Summary
    EudraCT Number:2011-003062-32
    Sponsor's Protocol Code Number:B1271004
    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:2011-11-22
    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 number2011-003062-32
    A.3Full title of the trial
    A RANDOMIZED PHASE 2 NON-COMPARATIVE STUDY OF THE EFFICACY OF PF-04691502 AND PF-05212384 IN PATIENTS WITH RECURRENT ENDOMETRIAL CANCER
    Estudio de fase 2, aleatorizado y no comparativo, para evaluar la eficacia de PF-04691502 y PF-05212384 en pacientes con cáncer de endometrio recurrente.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 comparative study of two investigational agents, PF04681502 and PF05212384 respectively, in women with advanced tumour of the uterus.
    Estudio comparativo de fase 2 de dos moleculas, PF04681502 y PF05212384 respectivamente, en mujeres con cancer avanzado de endometrio recurrente
    A.4.1Sponsor's protocol code numberB1271004
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01420081
    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 SponsorPFIZER SLU
    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 supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021
    B.5.5Fax number0013037391119
    B.5.6E-mailClincialTrials.govCallCenter@Pfizer.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.3.2Product code PF-04691502
    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 INNPF-04691502
    D.3.9.2Current sponsor codePF-04691502
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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.3.2Product code PF-04691502
    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 INNPF-04691502
    D.3.9.2Current sponsor codePF-04691502
    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.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.3.2Product code PF-05212384
    D.3.4Pharmaceutical form Lyophilisate 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 INNPF-05212384
    D.3.9.2Current sponsor codePF-05212384
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    ENDOMETRIAL CANCER RECURRENT
    Cáncer de endometrio recurrente
    E.1.1.1Medical condition in easily understood language
    advanced tumour of the uterus
    Tumor avanzado del utero
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level PT
    E.1.2Classification code 10014736
    E.1.2Term Endometrial cancer recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - Arm A: To assess the clinical benefit rate (CBR) of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer which is classified as PI3K basal.
    - Arm B: To assess the clinical benefit rate of the intravenous PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K basal.
    - Arm C: To assess the clinical benefit rate of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer which is classified as PI3K activated.
    - Arm D: To assess the clinical benefit rate of the intravenous PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K activated.
    - Grupo A: Evaluar la tasa de beneficio clinico (TBC) de PF-04691502, inhibidor oral de la PI3K/mTOR, en pacientes con cáncer de endometrio recurrente clasificado como PI3K basal.
    - Grupo B: Evaluar la TBC de PF-05212384, inhibidor IV de PI3K/mTOR, en pacientes con cáncer de endometrio recurrente clasificado como PI3K basal.
    - Grupo C: Evaluar la TBC de PF-04691502, inhibidor oral de la PI3K/mTOR, en pacientes con cáncer de endometrio recurrente clasificado como PI3K activada.
    - Grupo D: Evaluar la TBC de PF-05212384, inhibidor IV de PI3K/mTOR, en pacientes con cáncer de endometrio recurrente clasificado como PI3K activada.
    E.2.2Secondary objectives of the trial
    - To evaluate the anti-tumor activity of PF-04691502 and PF-05212384 individually in patients with PI3K basal and PI3K activated tumors.
    - To further characterize the safety of PF-04691502 and PF-05212384 individually.
    - To characterize the pharmacokinetics for PF-04691502 and PF-05212384 individually.
    - To characterize genetic and protein biomarkers of PI3K pathway alterations (PIK3CA mutation, PTEN protein levels, etc) in FFPE tumor specimens.
    - To explore the modulation of PI3K and mTOR pathways in pre and post dosing biopsies.
    - Evaluar la actividad antitumoral de PF-04691502 y PF-05212384 por separado en pacientes con tumores con PI3K basal y PI3K activada
    - Caracterizar mejor la seguridad de PF-04691502 y PF-05212384 por separado.
    - Caracterizar la farmacocinética de PF-04691502 y PF-05212384 por separado.
    - Caracterizar biomarcadores genéticos y proteicos de las alteraciones de la vía PI3K (mutación en PIK3CA, concentraciones de proteína PTEN, etc) en muestras de tumor FFEP.
    - Explorar la modulación de las vías de la PI3K y de mTOR en biopsias antes y después de la administración de la dosis.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MOLECULAR PROFILING SUPPLEMENT- EXPLORATORY RESEARCH SAMPLES FOR PFIZER?S BIOBANK "A RANDOMIZED PHASE 2 NON-COMPARATIVE STUDY OF THE EFFICACY OF PF-04691502 AND PF-05212384 IN RECURRENT ENDOMETRIAL CANCER" Version 23 June 2011.
    Objetive:
    The primary objective of this additional research component is to collect, store, and use samples to investigate possible associations between genomic and metabonomic variation:
    ?In relation to response to the study drugs, and
    ?In relation to characteristics of the disease/condition under study in the associated clinical trial, and related conditions.
    SUPLEMENTO DE PERFIL MOLECULAR- MUESTRAS PARA EL BIOBANCO DE INVESTIGACIÓN EXPLORATORIA DE PFIZER
    "ESTUDIO DE FASE 2, ALEATORIZADO Y NO COMPARATIVO, PARA EVALUAR LA EFICACIA DE PF-04691502 Y PF-05212384 EN PACIENTES CON CÁNCER DE ENDOMETRIO RECURRENTE" Version 23 de Junio de 2011
    Objetivo:
    El objetivo principal de esta investigación complementaria es obtener, almacenar y utilizar muestras para investigar las posibles asociaciones entre la variación genómica y metabolómica:
    ? En relación con la respuesta a los fármacos del estudio y
    ? En relación con las características de la enfermedad o trastorno que se estudia en el ensayo clínico asociado y de otros procesos relacionados.
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
    1. Women aged >=18 years.
    2. Histologically or cytologically confirmed diagnosis of endometrial carcinoma.
    3. Recurrent endometrial cancer that is not amenable to curative surgery and/or radiation.
    4. All patients must have tumor tissue available for central analysis of PI3K pathway activation status, performed by the sponsor-identified central laboratory prior to enrollment. Formalin fixed paraffin embedded (FFPE) block preferred, but freshly cut slides are acceptable.
    5. Disease progression on or following a platinum containing chemotherapy regimen (alone or in combination with radiation or hormonal therapy) for the treatment of endometrial cancer in the adjuvant or metastatic setting. Patients must not have progression during or immediately following (within 3 months) this regimen.
    6. At least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, V 1.1. Lesion must not have been previously irradiated.
    7. Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 (not declining within 2 weeks prior to signing of informed consent).
    8. Adequate Bone Marrow Function, including:
    a. Absolute Neutrophil Count (ANC) >= 1,500/mm3 or >=1.5 x 1000000000/L.
    b. Platelets >=100,000/mm3 or >=100 x 1000000000/L.
    c. Hemoglobin >=9 g/dL.
    9. Adequate Renal Function, including:
    a. Serum creatinine <=1.5 x upper limit of normal (ULN) or estimated creatinine clearance >= 60 ml/min as calculated using the method standard for the institution.
    10. Adequate Liver Function, including:
    a. Total serum bilirubin <=1.5 x ULN or <=1.0 mg/dL.
    b. Aspartate and Alanine Aminotransferase (AST & ALT) <=2.5 x ULN; <=5.0 x ULN if there is liver involvement.
    c. Alkaline phosphatase <=2.5 x ULN; (<=5 x ULN in case of bone metastasis).
    11. Adequate blood glucose control, as evidenced by HbA1c <8%.
    12. Adequate Cardiac Function, including 12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention.
    13. Resolved acute effects of any prior therapy to baseline severity or Grade <=1 CTC AE except for AEs not constituting a safety risk by investigator judgement.
    14. Serum/urine pregnancy test (for females of childbearing potential) negative within 72 hours of starting treatment.
    15. Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment.
    16. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    17. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures, including completion of patient reported outcomes.
    Las pacientes deberán cumplir todos los criterios de inclusión siguientes para poder participar en el estudio:
    1.Mujeres de >= 18 años.
    2.Diagnóstico de carcinoma de endometrio confirmado por histología o citología.
    3.Cáncer de endometrio recurrente no susceptible de cirugía y/o radioterapia curativa.
    4.Todas las pacientes deben tener antes de la inclusión tejido tumoral disponible para un análisis central del estado de activación de la vía PI3K en el laboratorio central identificado por el promotor. Se prefieren los tejidos fijados en formaldehido y embebidos en parafina (FFEP), pero son aceptables las preparaciones en fresco.
    5.Progresión de la enfermedad durante o después de una pauta de quimioterapia con platino (solo o en combinación con radioterapia u hormonoterapia) para el tratamiento del cáncer de endometrio en el contexto adyuvante o metastásico. Las pacientes no deben presentar progresión durante o inmediatamente después (en los 3 meses) de esa pauta.
    6.Como mínimo una lesión mensurable, según los criterios de evaluación de la respuesta en tumores sólidos (RECIST), V 1.1. La lesión no debe haberse irradiado previamente.
    7.Estado 0 ó 1 del Eastern Cooperative Oncology Group (ECOG) (que no haya declinado dentro de las 2 semanas anteriores a la firma del consentimiento informado). Apéndice 4.
    8.Función adecuada de la médula ósea, lo que incluye:
    a.Recuento absoluto de neutrófilos (RAN) >= 1.500/mm3 o >= 1,5 x 109/l;
    b.Recuento de plaquetas >=100.000/mm3 o >=100 x 109/l;
    c.Hemoglobina >= 9 g/dl.
    9.Función renal adecuada, lo que incluye:
    a.Creatinina sérica <= 1,5 x límite superior normal (LSN) o aclaramiento de creatinina estimado >= 60 ml/min, calculado con el método habitual del centro.
    10.Función hepática adecuada, lo que incluye:
    a.Bilirrubina sérica total <= 1,5 x LSN o <= 1,0 mg/dl.
    b.Aspartato y alanina aminotransferasa (ALT y AST) <= 2,5 x LSN; <= 5.0 x LSN si hay afectación hepática.
    c.Fosfatasa alcalina <= 2,5 x LSN; (<= 5 x LSN en caso de metástasis ósea).
    11.Control adecuado de la glucemia, evidenciado por una HbA1c < 8%.
    12.Función cardíaca adecuada, lo que incluye:
    a.Electrocardiograma (ECG) de 12 derivaciones con trazado normal o cambios sin importancia clínica que no precisan intervención médica.
    13.Efectos agudos de cualquier tratamiento previo resueltos hasta la intensidad basal o un grado <= 1 de los CTCAE, salvo en caso de AA que no supongan un riesgo para la seguridad a criterio del investigador.
    14.Prueba de embarazo en suero/orina (en mujeres con potencial fértil) negativa en las 72 horas previas al comienzo del tratamiento.
    15.Las mujeres deben estar esterilizadas por métodos quirúrgicos, ser posmenopáusicas o comprometerse a usar métodos anticonceptivos eficaces durante el período del ensayo y durante al menos 90 días después de completar el tratamiento.
    16.Disponer del documento de consentimiento informado, firmado y fechado en persona, que indique que se ha informado a la paciente (o a su representante legal) de todos los aspectos pertinentes del estudio.
    17.Disposición y capacidad para cumplir las visitas programadas, los planes de tratamiento, las pruebas analíticas y otros procedimientos del estudio, incluida la cumplimentación de los resultados comunicados por las pacientes.
    E.4Principal exclusion criteria
    Patients presenting with any of the following will not be included in the study:
    1. Patients who are investigational site staff members or patients who are Pfizer employees directly involved in the conduct of the trial.
    2. More than 2 prior cytotoxic chemotherapy regimens for endometrial carcinoma. Prior hormonal therapy is acceptable.
    3. Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
    4. Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), hormonal, biological or investigational agents within 2 weeks of first dose of study drug (6 weeks for mitomycin C or nitrosoureas).
    5. Any surgery (not including minor procedures such as lymph node biopsy, needle biopsy, and/or placement of port-a-cath) within 4 weeks of first dose of study drug; or not fully recovered from any side effects of previous procedures.
    6. Prior therapy with an agent that is known or proposed to be active by action on PI3K, and/or mTOR, and/or AKT.
    7. Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors. Because inhibition of CYP3A4 isoenzymes may increase study drug exposure leading to a potential increases in toxicities, the use of known strong inhibitors (Strong CYP3A4 Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, erythromycin, clarithromycin, telithromycin, varapamil, indinavir, saquinavir, ritonavir, nelfinavir, nefazodone, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine, troleandomycin, mibefradil, conivaptan) are not permitted from 10 days prior to the first dose of study drug until study treatment discontinuation.
    8. Current or anticipated need for food or drugs that are known potent CYP3A4 inducers. Study drug metabolism may be induced when taking strong CYP3A4 inducers (eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St. John?s Wort) resulting in reduced plasma concentrations. Therefore co administration of study drug in combination with these and other strong CYP3A4 inducers is not permitted from 10 days prior to the first dose of stud drug until study treatment discontinuation.
    9. Concurrent administration of herbal preparations.
    10. Breast feeding: No studies have been conducted in humans to assess the impact of PF 04691502 or PF-05212384 on milk production, its presence in breast milk and its effects on the breast fed child. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, lactating female patients are excluded from this study.
    11. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet or capsule form and malabsorption syndrome.
    12. Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol.
    13. Other severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the patient inappropriate for entry into this trial.
    14. Participation in other studies within 2 weeks before the current study begins and/or during study participation.
    No se incluirá en el estudio a las pacientes que cumplan cualquiera de las condiciones siguientes:
    1.Pacientes que sean miembros del personal del centro de investigación o empleados de Pfizer directamente implicados en la realización del ensayo.
    2.Más de 2 pautas previas de quimioterapia citotóxica para el carcinoma de endometrio. Se acepta el tratamiento hormonal previo.
    3.Pacientes con metástasis cerebrales activas conocidas. Las pacientes con metástasis cerebrales diagnosticadas previamente podrán participar si han completado su tratamiento del SNC y se han recuperado de los efectos agudos de la radioterapia o la cirugía antes del inicio de la medicación del estudio, han interrumpido el tratamiento con corticosteroides de estas metástasis durante al menos 4 semanas y están neurológicamente estables.
    4.Administración de quimioterapia, radioterapia (distinta de la radioterapia paliativa de lesiones que no vayan a ser objeto de seguimiento para evaluación tumoral en este estudio, es decir, lesiones no diana), productos hormonales, biológicos o fármacos en investigación en las 2 semanas anteriores a la primera dosis de fármaco del estudio (6 semanas para la mitomicina C o las nitrosoureas).
    5.Cualquier intervención quirúrgica (excepto las de cirugía menor, como biopsia de ganglios linfáticos, biopsia con aguja o colocación de catéter) en las 4 semanas previas a la primera dosis de fármaco del estudio, o ausencia de recuperación plena de los efectos secundarios de intervenciones previas.
    6.Tratamiento previo con un fármaco que se sepa o se sospeche que es activo por sus efectos sobre PI3K y/o mTOR y/o AKT.
    7.Uso actual o necesidad prevista de alimentos o fármacos que sean inhibidores potentes de la CYP3A4. Dado que la inhibición de la CYP3A4 puede aumentar la exposición al fármaco del estudio, con la consiguiente posibilidad de inducción de aumentos de la toxicidad, no se permite el uso de inhibidores potentes conocidos (inhibidores potentes de la CYP3A4: zumo de pomelo o pomelo o cítricos relacionados con él (p. ej., naranjas amargas), ketoconazol, miconazol, itraconazol, voriconazol, posaconazol, eritromicina, claritromicina, telitromicina, verapamilo, indinavir, saquinavir, ritonavir, nelfinavir, nefazodona, lopinavir, atazanavir, amprenavir, fosamprenavir y delavirdina, troleandomicina, mibefradilo, conivaptán) desde 10 días antes de la primera dosis de fármaco del estudio hasta la interrupción de este tratamiento.
    8.Necesidad actual o prevista de alimentos o fármacos que sean inductores potentes conocidos de la CYP3A4. Al tomar inductores potentes de la CYP3A4 (p. ej., fenobarbital, rifampicina, fenitoína, carbamazepina, rifabutina, rifapentina, clevidipino, hipérico (hierba de San Juan)), puede inducirse metabolismo del fármaco del estudio, con la reducción consiguiente de las concentraciones plasmáticas. Por consiguiente, no se permite la administración conjunta del fármaco del estudio y de estos y otros inductores potentes de la CYP3A4 desde 10 días antes de la primera dosis de fármaco del estudio hasta la interrupción de este tratamiento.
    9.Administración concomitante de preparados de fitoterapia.
    10.Lactancia materna: No se han realizado estudios en seres humanos para valorar los efectos de PF-04691502 o PF-05212384 en la producción de leche, su presencia en la leche materna y sus efectos en el lactante. Dado que los fármacos se excretan comúnmente en la leche materna y que existe un potencial de reacciones adversas graves en los lactantes, las pacientes lactantes no podrán participar en este estudio.
    11.Cualquier anomalía digestiva de importancia clínica que pueda alterar la toma, el tránsito o la absorción del fármaco del estudio, como la incapacidad de tomar medicación oral en forma de comprimidos o cápsulas y el síndrome de malabsorción.
    12.Cualquier trastorno mental que limite la comprensión o la concesión del consentimiento informado y el cumplimiento de los requisitos de este protocolo.
    13.Otro proceso médico o anomalía analítica aguda o crónica intensa que pueda aumentar el riesgo asociado a la participación en el ensayo o a la administración del producto en investigación o interferir en la interpretación de los resultados del ensayo y que, en opinión del investigador, haría inadecuada la inclusión de la paciente en este ensayo.
    14.Participación en otros estudios durante las 2 semanas anteriores al inicio del estudio actual y/o durante la permanencia en él.
    E.5 End points
    E.5.1Primary end point(s)
    ? Clinical Benefit Response (CBR) (CR+PR+SD 16 weeks)
    ?Respuesta de beneficio clínico (TBC) [RC+RP+EE 16 semanas].
    E.5.1.1Timepoint(s) of evaluation of this end point
    Radiological tumor assessments will be conducted at baseline, during treatment as specified in the Schedule of Events, whenever disease
    progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from
    the study (if not done in the previous 6 weeks).
    Assessment of response will be made using RECIST version 1.1.
    Se realizarán evaluaciones radiológicas del tumor en el período basal, durante el tratamiento según se especifica en el Calendario de actividades, cuando se sospeche progresión de la enfermedad (p. ej., deterioro sintomático) y en el momento de la retirada del estudio (si no se han realizado en las 6 semanas anteriores). La valoración de la respuesta se hará mediante la versión 1.1 de los RECIST.
    E.5.2Secondary end point(s)
    ? Objective tumor response, as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1.
    ? Overall Survival (OS).
    ? Progression Free Survival (PFS).
    ? PFS at 6 months.
    ? Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0), timing, seriousness and relationship to study therapy.
    ? Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
    ? Vital signs.
    ? Expression and/or phosphorylation in biopsied tumor tissue of PI3K pathway proteins (such as p-AKT, p-S6, p-S6K,p- mTOR, p-PRAS40, stathmin).
    ? Gene and/or protein expression biomarkers in biopsied tumor tissue relating to PI3K and/or mTOR pathway activation, such as PIK3CA and PIK3R1 mutations, PTEN protein levels, PIK3CA gene amplification, stathmin.
    ? Pharmacokinetics of PF-04691502 and PF-05212384.
    ? Respuesta tumoral objetiva, valorada mediante los Criterios de evaluación de la respuesta de tumores sólidos (RECIST), versión 1.1.
    ? Supervivencia global (SG)
    ? Supervivencia libre de progresión (SLP).
    ? SLP a los 6 meses.
    ? Acontecimientos adversos, caracterizados por el tipo, frecuencia, intensidad (graduada según los CTCAE del NCI v. 4.0), cronología, gravedad y relación con el tratamiento del estudio;
    ? Anomalías analíticas, caracterizadas por el tipo, frecuencia, intensidad (graduada según los CTCAE del NCI v. 4.0) y cronología;
    ? Constantes vitales.
    ? Expresión y/o fosforilación en tejido tumoral biopsiado de proteínas de la vía PI3K (como p-Akt, p-S6, p-S6K, p-mTOR, p-PRAS40, estatmina).
    ? Biomarcadores de expresión génica o proteica en tejido tumoral biopsiado en relación con la activación de la vía PI3K y/o mTOR, en forma de mutaciones en PIK3CA y PIK3R1, concentraciones de proteína PTEN, amplificación del gen PIK3CA, estatmina.
    ? Farmacocinética de PF-04691502 y PF05212384.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Trial procedures are described in the ASSESSMENTS Section
    and in the Schedule of Activities. Safety laboratory studies (hematology, blood chemistry, urinalysis, pregnancy test (except for screen/baseline) if needed) and tumor assessments may
    be done up to 96 hours prior to scheduled Day 1 visit on any cycle to facilitate availability of results to investigator at the time of clinic visit.
    Exploratory "Omics" analyses will be conducted as described in the Molecular Supplement.
    Los procedimientos del estudio están descritos en la sección EVALUACIONES y en el Calendario de Actividades. Las evaluaciones de seguridad de laboratorio (hematología, bioquímica en sangre, urianálisis, prueba de embarazo [(excepto para la selección/basal), si se precisa] y las evaluaciones tumorales pueden hacerse hasta 96 horas antes de la visita programada del día 1 en cualquier ciclo para facilitar que el investigador disponga de los resultados en el momento de la visita clínica.

    Los análisis exploratorios de "ómica" se realizarán según se describe en el Suplemento de Perfil Molecular.
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA42
    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
    Canada
    Germany
    Japan
    Philippines
    Poland
    Russian Federation
    Slovakia
    Spain
    Taiwan
    Turkey
    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
    End of Trial in all participating countries is defined as last patient having the End of Treatment visit.
    Se define como fin del ensayo en todos los países participantes la visita de fin del tratamiento del último paciente..
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial 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: 93
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 159
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 142
    F.4.2.2In the whole clinical trial 252
    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)
    none
    Ninguno
    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 Decision2012-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-12-25
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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