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    Summary
    EudraCT Number:2014-004982-25
    Sponsor's Protocol Code Number:BET115521
    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:2015-06-01
    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 number2014-004982-25
    A.3Full title of the trial
    A phase I/II open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in subjects with NUT midline carcinoma (NMC) and other cancers
    Estudio de fase I/II, abierto, de escalado de dosis para investigar la seguridad, farmacocinética, farmacodinámica y actividad clínica de GSK525762 en sujetos con carcinoma de la línea media-NUT (CLM-NUT) y otros cánceres
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study using the drug GSK525762 in Subjects with cancer
    Estudio clínico con el fármaco GSK525762 en pacientes con cáncer.
    A.4.1Sponsor's protocol code numberBET115521
    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 SponsorGlaxoSmithKline, 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 supportGlaxoSmithKline
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointCentro de Información
    B.5.3 Address:
    B.5.3.1Street AddressC/Severo Ochoa, 2 (P.T.M.)
    B.5.3.2Town/ cityTres Cantos (Madrid)
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34902202700
    B.5.5Fax number34918070479
    B.5.6E-mailes-ci@gsk.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 nameGSK525762
    D.3.2Product code GSK525762
    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 INNNot applicable
    D.3.9.1CAS number Not applicab
    D.3.9.2Current sponsor codeGSK525762
    D.3.9.3Other descriptive nameGSK525762
    D.3.9.4EV Substance CodeSUB122475
    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.3.1Product nameGSK525762
    D.3.2Product code GSK525762
    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 INNNot applicable
    D.3.9.1CAS number Not applicab
    D.3.9.2Current sponsor codeGSK525762
    D.3.9.3Other descriptive nameGSK525762
    D.3.9.4EV Substance CodeSUB122475
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameGSK525762
    D.3.2Product code GSK525762
    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 INNNot applicable
    D.3.9.1CAS number Not applicab
    D.3.9.2Current sponsor codeGSK525762
    D.3.9.3Other descriptive nameGSK525762
    D.3.9.4EV Substance CodeSUB122475
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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
    NUT Midline Carcinoma and other solid tumors.
    Carcinoma de línea media-NUT y otros tumores sólidos.
    E.1.1.1Medical condition in easily understood language
    NUT Midline Carcinoma and other solid tumors
    Carcinoma de línea media-NUT y otros tumores sólidos.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10007284
    E.1.2Term Carcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To determine the safety, tolerability and maximum tolerated dose (MTD) of GSK525762 in subjects 16 years or older following QD and/or BID dosing schedules.
    - To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.
    - [US Clinical sites only] To evaluate, after single dose administration, the relative bioavailability of the GSK525762 besylate tablet compared to the amorphous free-base tablet, the effect of high-fat high-calorie meal on the bioavailability of the besylate tablet and the dose proportionality of two doses of GSK525762 administered as the besylate tablets.
    - Determinar la seguridad, tolerabilidad y dosis máxima tolerada (DMT) de GSK525762 en sujetos de 16 años de edad o más tras pautas posológicas QD y/o BID.
    - Evaluar la actividad clínica de GSK525762 en CNM y otros tumores sólidos.
    - Evaluar, tras la administración de una dosis única, la biodisponibilidad relativa del comprimido de besilato de GSK525762 en comparación con el comprimido amorfo de base libre, el efecto de una comida rica en grasas y calorías sobre la biodisponibilidad del comprimido de besilato y la proporcionalidad de la dosis de dos dosis de GSK525762 administrado como comprimidos de besilato.
    E.2.2Secondary objectives of the trial
    - To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years or older following QD and/or BID dosing schedules.
    - To evaluate cardiac safety, including the potential for QTcF changes with GSK525762 and to assess PK/QTcF relationship following QD and/or BID dosing schedules.
    - To evaluate the exposure response (pharmacokinetic/pharmacodynamic [PK/PD]) relationship between GSK525762 and safety and efficacy parameters following QD and/or BID dosing schedules.

    - To evaluate the effect of treatment with GSK525762 on tumor growth and survival.
    - Caracterizar la farmacocinética (FC) de GSK525762 en sujetos de 16 años de edad o más tras pautas posológicas QD y/o BID.
    - Evaluar la seguridad cardíaca, incluido el potencial de cambios QTcF con GSK525762 y evaluar la relación FC/QTcF tras pautas posológicas QD y/o BID.
    - Evaluar la relación exposición-respuesta (farmacocinética/farmacodinámica [FC/FD]) entre GSK525762 y los parámetros de seguridad y eficacia tras pautas posológicas QD y/o BID.
    - Evaluar el efecto del tratamiento con GSK525762 sobre el crecimiento tumoral y la supervivencia.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: Besylate Sub-Study [US Clinical sites only]
    Objective: To determine the relative bioavailability (BA), food effect, and dose proportionality of the besylate formulation of GSK525762 at or near the MTD

    Title: Pharmacogenetic Research

    Objectives: The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to GSK525762. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with GSK525762 that may be attributable to genetic variations of subjects, the following objectives may be investigated ? the relationship between genetic variants and study treatment with respect to:

    - Pharmacokinetics and/or pharmacodynamics of study treatment,

    - Safety and/or tolerability, and

    - Efficacy.
    Subestudio de besilato [solo para centros de EE.UU.]
    Estudio farmacogenético:
    El objetivo de la investigación PGx (si hay una variación inesperada o
    inexplicable potencial) es averiguar la posible relación genética con el
    manejo o la respuesta a GSK525762. Si parece que se dispone de una
    variabilidad potencial con respecto a la respuesta en cualquier momento
    en este estudio clínico o en una serie de estudios clínicos con
    GSK525762 que puede atribuirse a las variaciones genéticas de los
    pacientes, es necesario investigar los objetivos a continuación: la
    relación entre las variantes genéticas y el tratamiento del estudio
    respecto a:
    - La farmacocinética y/o farmacodinámica del tratamiento del estudio,
    - Seguridad y/o tolerabilidad y
    - Eficacia.
    E.3Principal inclusion criteria
    1. Male or female 16 years or older, at the time of signing the informed consent.
    2. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. If the subject is less than 18 years old, an Assent form and parental/guardian Consent form (replacing "you will" with "your child will" will be required).
    3. Diagnosis of one of the following:
    Part 1 Only:
    - NUT Midline Carcinoma based on ectopic expression of NUT protein as determined by IHC and/or detection of NUT gene translocation as determined by FISH. Subjects may be treatment naïve or have had prior therapy.
    - SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC, and any other solid tumor which has been confirmed by clinical testing to be MYCN amplified (defined as a MYCN gene copy number gain of >=5). Subjects should have tumor progression after receiving at least one prior standard/approved chemotherapy, or where there is no approved therapy, or where standard therapy is refused.
    Part 2 Only:
    - NUT Midline Carcinoma as diagnosed by the Central Laboratory. Subjects may be treatment naïve or have had prior therapy.
    - SCLC, CRPC, TNBC and ER+BC
    4. Subjects with solid tumors, with the exception of CRPC, must demonstrate measurable disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet the RECIST v1.1 criteria for measurable disease, but have evaluable disease may be considered for enrollment after discussion with the GSK medical monitor.
    5. All prior treatment- related toxicities must be CTCAE (Version 4.0) <=Grade 1 (except alopecia and peripheral neuropathy) at the time of treatment allocation.
    6. ECOG Performance Status score of 0 to 2 for subjects with NMC; 0-1 for subjects with other tumor types.
    7. Adequate organ function as defined in Table 8. See table in the protocol
    8. Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
    9. A female subject is eligible to participate if she is of:
    - Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 MlU/ml and estradiol <40 pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
    - Child-bearing potential and agrees to use one of the contraception methods (described in Section 9.1) for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until at least 4 weeks after the last dose of study medication.
    - Negative serum pregnancy test <=7 days prior to first study drug dose.
    - Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 5 half-lives of GSK525762 or at least 28 days (whichever is longer) following the last dose of study treatment.
    10. Male subjects must agree to use one of the methods of contraception specified. This method must be used from the time of the first dose of study medication until least 16 weeks after the last dose of study medication.
    Specific Eligibility Criteria for Part 2 CRPC Expansion Cohort:
    11. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, surgically castrated or continuously medically castrated (for more than or equal to 8 weeks prior to prescreening)
    12. Persistent disease with evidence of disease progression following standard therapy(ies) including prior treatment with androgen/androgen receptor directed therapy, including enzalutamide and/or abiraterone
    13. Ongoing androgen deprivation therapy with a serum testosterone level <1.7 nmol/L or <50 ng/dL
    14. PSA levels more than or equal to 2.0 ng/mL
    1. Hombre o mujer de 16 años de edad o más, en el momento de la firma del consentimiento informado.
    2. Capaz de dar su consentimiento informado por escrito, lo que incluye el cumplimiento de los requisitos y restricciones que figuran en el formulario de consentimiento.
    3. Diagnóstico de uno de los siguientes:
    Únicamente en la parte 1:
    - Carcinoma NUT de línea media basado en la expresión de la proteína NUT determinado por IHQ y/o detección de translocación del gen NUT determinado por FISH. Los sujetos pueden no haber recibido tratamiento previo o haberlo recibido.
    - CPM, CCR, NB, CMTN, CM RE positivo, CPRC, CPNM y cualquier otro tumor sólido con amplificación de MYCN confirmado por pruebas clínicas (definido como ganancia de número de copias génicas MYCN >=5). Los sujetos deben haber experimentado progresión del tumor tras haber recibido al menos una quimioterapia estándar/aprobada, o en los casos en que no haya ningún tratamiento aprobado, o el tratamiento estándar es rechazado.
    Únicamente en la parte 2:
    - Carcinoma NUT de línea media diagnosticado por el laboratorio central. Los sujetos pueden no haber recibido tratamiento previo o haberlo recibido.
    - CPM, CPRC, CMTN y CMRE+
    4. Los sujetos con tumores sólidos, con la excepción de CPRC, deben demostrar enfermedad medible, conforme a los criterios RECIST v1.1.
    5. Todas las toxicidades relacionadas con algún tratamiento previo deben ser CTCAE (versión 4.0 ) <=grado 1 (excepto alopecia y neuropatía periférica) en el momento de la asignación del tratamiento.
    6. Puntuación de 0 a 2 en la escala del estado funcional ECOG en el caso de sujetos con CNM; 0-1 en el caso de sujetos con otros tipos de tumores.
    7. Función orgánica adecuada como se define en la Tabla 8 del Protocolo.
    8. Capaz de tragar y retener medicamentos administrados por vía oral y sin ninguna anomalía gastrointestinal clínicamente significativa que pueda alterar la absorción como síndrome de malabsorción o resección importante del estómago o intestinos.
    9.Una mujer es elegible para participar si:
    - No tiene capacidad para concebir definida como mujer premenopáusica con ligadura de trompas o histerectomía documentadas; o postmenopáusica definida como 12 meses de amenorrea espontánea (en todos los casos dudosos una muestra de sangre con hormona estimulante del folículo (FSH) >40 MlU/ml y estradiol < 40 pg/ml (< 140 pmol/l) en simultáneo es confirmatoria). Las mujeres que reciban terapia hormonal sustitutiva (THS) y cuyo estado menopáusico sea dudoso deberán utilizar uno de los métodos anticonceptivos si desean continuar con su THS durante el estudio. En caso contrario, deberán interrumpir la THS para permitir la confirmación del estado postmenopáusico antes de la inclusión en el estudio. En la mayoría de las formas de la THS, deberán transcurrir al menos de 2 a 4 semanas entre el cese de la terapia y la extracción de la sangre; este intervalo depende del tipo y la dosis de la THS.
    - Tiene capacidad para concebir y acepta utilizar uno de los métodos anticonceptivos (descritos en la sección 9.1) durante un período de tiempo adecuado (determinado por la ficha técnica del producto o el investigador) antes de iniciar la administración para reducir suficientemente el riesgo de embarazo en ese momento.
    - Prueba de embarazo en suero negativa <=7 días antes de la primera dosis del fármaco del estudio.
    - Las mujeres en período de lactancia deben interrumpir la misma antes de la primera dosis del tratamiento del estudio y deben abstenerse durante todo el período de tratamiento y durante 5 semividas de GSK525762 o al menos 28 días (lo que ocurra más tarde) tras la última dosis del tratamiento del estudio.
    10. Los sujetos varones deben aceptar utilizar uno de los métodos anticonceptivos especificados. Este método debe utilizarse desde el momento de la primera dosis de medicación del estudio hasta al menos 16 semanas después de la última dosis de medicación del estudio.
    Criterios de selección específicos para la Cohorte de Expansión CPRC de la parte 2
    11. Diagnóstico de adenocarcinoma de próstata histológicamente o citológicamente confirmado, castrados quirúrgicamente o médicamente castrados de forma continua (durante >=8 semanas antes de la preselección)
    12. Enfermedad persistente con evidencia de progresión de la enfermedad tras terapia(s) estándar incluyendo el tratamiento previo con terapia dirigida a receptores de andrógenos/andrógenos, incluyendo enzalutamida y/o abiraterona.
    13. Tratamiento de privación androgénica en curso con un nivel de testosterona en suero <1,7 nmol/l o <50 ng/dl
    14. Niveles APE >=2,0 ng/ml
    E.4Principal exclusion criteria
    1. Primary malignancy of the central nervous system, or malignancies related to HIV or solid organ transplant. History of known HIV. History of known Hepatitis B surface antigen or positive Hepatitis C antibody (confirmed by RIBA).
    2. Prior treatments usage as defined:
    a. Use of an investigational anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior to the first dose of the investigational products.
    b. A minimum of 14 days between termination of the investigational drug and administration of GSK525762.
    c. Any therapy related toxicities must also have resolved to Grade 1 or less. Note that an investigational drug is defined as a drug without an approved oncologic indication.
    d. Chemotherapy, radiotherapy, anti-neoplastic antibody or targeted therapy or immunotherapy within 14 days, major surgery within 28 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of the investigational product.
    e. Anti-androgen (e.g., bicalutamide) therapies for prostate cancer must be stopped 4 weeks prior to enrollment. Second line hormone therapies such as enzalutamide, abiraterone, or orteronel should be stopped 2 weeks prior to enrollement. Subjects with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Subjects with prostate cancer may also remain on low-dose prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.
    3. Current use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of GSK525762. Low dose (prophylactic) low molecular weight heparin (LMWH) is permitted. In addition, INR must be monitored in accordance with local institutional practices.
    4. Current use of a prohibited medication or requires any of these medications during treatment with the investigational drugs (details will be available in Section 8.3). This includes excluding current medications known or suspected to be associated QT prolongation. In addition, any subject who may require a QT prolonging medication while on trial should not be enrolled.
    5. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
    6. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
    NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >1months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Subject treated with gamma knife the can be enrolled 2 weeks postprocedure as long as there are no post-procedure complications/stable. In addition, subjects treated or currently taking enzyme-inducing anticonvulsant (EIAC) are allowed on study.
    7. Cardiac abnormalities as evidenced by any of the following:
    - History or current untreated clinically significant uncontrolled arrhythmias.
    - Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block
    - Presence of cardiac pacemaker
    - History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA).
    - History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
    8. Any of the following EKG findings:
    - Baseline QTcF interval >=450 msec
    - Any clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
    9. GSK525762 is a benzodiazepine class molecule. Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs chemically related to the investigational drug.
    10. Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
    11. History of major gastrointestinal bleeding within the last 6 months. Any evidence of active gastrointestinal bleeding excludes the subject.
    12. Besylate Sub-Study only [US Clinical sites only]: unable or unwilling to eat the FDA recommended high-fat high-calorie breakfast (two eggs fried in butter, two strips of bacon, 4 oz. of hash brown potatoes and 8 oz of whole milk) within the recommended 30 minutes.
    1. Neoplasia maligna primaria del sistema nervioso central, o neoplasias malignas relacionadas con el VIH o trasplante de órganos sólidos. Antecedentes conocidos de VIH. Antecedentes conocidos de antígeno de superficie de la hepatitis B o resultado positivo a anticuerpos contra la hepatitis C (confirmado por RIBA).
    2. Uso de tratamientos previos definido como:
    a. Uso de un fármaco contra el cáncer en investigación dentro de los 14 días o 5 semividas, lo que suponga más tiempo, antes de la primera dosis de los productos en investigación.
    b. Un mínimo de 14 días entre la finalización del producto en investigación y la administración de GSK525762.
    c. Cualquier toxicidad relacionada con el tratamiento también se debe haber resuelto a grado 1 o menos. Debe tenerse en cuenta que un fármaco en investigación se define como un fármaco sin indicación oncológica aprobada.
    d. Quimioterapia, radioterapia, terapia dirigida o antineoplásica con anticuerpos o inmunoterapia en los 14 días, cirugía mayor dentro en los 28 días (o 42 días para nitrosureas o mitomicina C previas) anteriores a la primera dosis del producto en investigación.
    e. Las terapias antiandrogénicas (p. ej., bicalutamida) para el cáncer de próstata deben detenerse 4 semanas antes de la inclusión. Las terapias hormonales de segunda línea como enzalutamida, abiraterona, o orteronel deben detenerse 2 semanas antes de inclusión. Los sujetos con cáncer de próstata deben seguir recibiendo agonistas o antagonistas de la hormona luteinizante liberadora de hormonas (LHRH). Los sujetos con cáncer de la próstata también pueden seguir recibiendo dosis bajas de prednisona o prednisolona (hasta 10 mg/día) y todavía ser elegibles para este estudio.
    3. Uso actual de anticoagulantes (p. ej., warfarina, heparina) a niveles terapéuticos en los 7 días anteriores a la primera dosis de GSK525762. Está permitida la administración de dosis bajas (profiláctico) de heparinas de bajo peso molecular (HBPM). Además, debe controlarse el INR de conformidad con las prácticas institucionales locales.
    4. Uso actual de un medicamento prohibido o si se requiere alguno de estos medicamentos durante el tratamiento con los fármacos en investigación (los detalles estarán disponibles en la sección 8.3). Esto incluye medicamentos actuales excluyentes de los que se sabe o sospecha que están asociados a la prolongación del QT. Además, todo sujeto que pueda necesitar un medicamento que prolongue el QT mientras participe en el ensayo no debe incluirse en el mismo.
    5. Evidencias de enfermedades graves o sistémicas no controladas (p. ej., enfermedad respiratoria inestable o no compensada, hepática, renal, cardíaca, o episodios de hemorragia clínicamente significativa). Toda enfermedad médica grave y/o inestable preexistente (aparte de la excepción anterior de neoplasias malignas), trastorno psiquiátrico, u otras afecciones que puedan interferir con la seguridad del sujeto, la obtención del consentimiento informado o el cumplimiento de los procedimientos del estudio, en opinión del investigador.
    6. Metástasis leptomeníngea o cerebral sintomática o sin tratar o compresión de la médula espinal.
    7. Anomalías cardíacas evidenciadas por cualquiera de los siguientes:
    - Antecedentes de arritmias o arritmias actuales no controladas y sin tratar clínicamente significativas.
    - Anomalías de la conducción o arritmias clínicamente importantes, sujetos con bloqueo de rama
    - Presencia de marcapasos cardíaco
    - Antecedentes o evidencia de insuficiencia cardíaca congestiva actual >=clase II definida por la NYHA.
    - Antecedentes de síndromes coronarios agudos (incluyendo angina inestable e infarto de miocardio), angioplastia coronaria, o colocación de stent en los últimos 3 meses.
    8. Cualquiera de los siguientes resultados en ECG:
    - Intervalo QTc en el momento basal >=450 mseg.
    - Cualquier evaluación ECG clínicamente significativa debe ser revisada por el cardiólogo del centro antes de la entrada en el estudio.
    9. GSK525762 es una molécula de clase benzodiacepina Cualquier reacción de hipersensibilidad grave inmediatamente conocida o tardía a GSK525762 o idiosincrasia a fármacos químicamente relacionados con el fármaco en investigación.
    10. Hemoptisis >6 ml en 24 horas en los últimos 28 días.
    11. Antecedentes de hemorragia gastrointestinal importante en los últimos 6 meses. Cualquier evidencia de hemorragia gastrointestinal excluye al sujeto.
    E.5 End points
    E.5.1Primary end point(s)
    - AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years or older
    - Assess overall response rate (RR) by RECIST 1.1 in NMC and other solid tumors.
    - PK parameter values for GSK525762 following single oral administration as amorphous free-base or besylate tablet
    - AA(s), AAG(s), reducciones o retrasos de las dosis, retiradas debido a toxicidades y cambios en las evaluaciones de seguridad (p. ej., parámetros analíticos, constantes vitales, ECG, cardiotoxicidad, gastrointestinal, etc.) para determinar la DMT en sujetos de 16 años de edad o más.
    -Evaluar la tasa de respuesta (TR) global mediante RECIST 1.1 en CNM y otros tumores sólidos.
    - Valores de los parámetros FC de GSK525762 tras la administración oral única como comprimido amorfo de base libre o comprimido de besilato.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1: Dose limiting toxicity will be evaluated during the first 4 weeks of treatment but all other safety parameters and adverse events are followed until the patient discontinues the study.

    Part 2: The response rate will be assessed until a subject has disease progression or terminates the study.
    Parte 1: La toxicidad limitante de la dosis se evaluará durante las 4 primeras semanas de tratamiento pero todas las evaluaciones de seguridad restantes y los acontecimientos adversos se seguirán hasta que el último paciente descontinúe en el estudio.
    Parte 2: La tasa de respuesta se evaluará hasta que un paciente tenga progresión de la enfermedad o finalice el estudio.
    E.5.2Secondary end point(s)
    - PK parameter values for GSK525762 following single and repeat-dose oral administration in subjects 16 years or older
    - Changes in cardiac safety including QTcF following single and repeat-dose oral administration GSK525762.
    - Progression free survival (PFS), time to response, duration of response, overall survival (OS), and exploratory analysis for antitumor response by various imaging modalities.
    - Valores de los parámetros FC de GSK525762 tras la administración oral de dosis únicas y repetidas en sujetos de 16 años de edad o más.
    - Cambios en la seguridad cardíaca incluyendo QTcF tras la administración oral de dosis únicas y repetidas de GSK525762.
    - Supervivencia libre de progresión (SLP), tiempo hasta la respuesta, duración de la respuesta, supervivencia global (SG) y análisis exploratorios de la respuesta antitumoral mediante diversas modalidades de diagnóstico por imágenes.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1: Subjects will be evaluated for secondary endpoints such as pharmacokinetics for the first 4 weeks, at Week 9, and every 8 weeks for subjects on study longer than 13 weeks.

    Part 2: Subjects will be evaluated for secondary endpoints for the first 4 weeks and subsequently at Week 5, Week 9, and Week 10. Subjects will then be evaluated 3 weeks after Week 13, and every 4 weeks thereafter.

    In both Part 1 and Part 2, subjects will receive study treatment until disease progression, death or unacceptable adverse event. A subject will be considered to have completed the study 2 years after the last treatment or if the subject dies or is still in follow-up at the time the study is closed or terminated, whichever is sooner.
    Parte 1: Los pacientes serán evaluados para las variables secundarias como la Pk durante las 4 primeras sems, en la sem 9 y cada 8 sems para sujetos que continúen en el estudio más de 13 sems.
    Parte 2: los sujetos serán evaluados para las variables segundarias durante las primeras 4 sems, en la sem 5, sem 9 y sem 10. Los sujetos serán entonces evaluados 3 sems tras la sem 13 y cada 4 sems posteriormente.
    Tanto en la parte 1 como en la parte 2, los sujetos recibirán el tto. del estudio hasta la progresión de la enfermedad, fallecimiento, o acontecimiento adverso no tolerable. Se considera que un sujeto ha completado el estudio 2 años después de la última dosis, si el sujeto fallece, o si está en seguimiento en el momento en el que el estudio se cierra o concluye (lo que suceda antes).
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    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 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 trial1
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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
    France
    Netherlands
    Spain
    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
    The end of the study date is defined as last subject last visit (contact).
    La fecha de final del estudio se define como la última visita del último sujeto (contacto).
    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 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Children (16 and 17 yr)
    Adolescentes (16 y 17 años)
    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 100
    F.4.2.2In the whole clinical trial 225
    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)
    Subjects may remain on study treatment until disease progression, death or unacceptable adverse event. After disease progression, subjects may be allowed to continue treatment with study drug if the Investigator strongly believes, and the Sponsor Medical Monitor concurs, that the subject could continue to receive benefit (for example in cases of an isolated new lesion, with the majority of the disease still under control).
    Los sujetos recibirán el tratamiento del estudio hasta la progresión de la enfermedad, muerte o acontecimientos adversos inaceptables. Tras la progresión de la enfermedad, se permitirá a los sujetos continuar el tratamiento con el fármaco del estudio si el investigador cree firmemente, y el monitor médico del promotor se muestra de acuerdo, que el sujeto podría continuar recibiendo beneficios (ej., en los casos de una nueva lesión aislada, con la mayoría de la enfermedad aún bajo control).
    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 Decision2015-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-29
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