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    Summary
    EudraCT Number:2013-000093-29
    Sponsor's Protocol Code Number:9785-CL-1121
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-05-08
    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 number2013-000093-29
    A.3Full title of the trial
    A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide with Trastuzumab in Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer
    Estudio de fase II, multicéntrico, abierto, para evaluar la eficacia y la seguridad de enzalutamida con trastuzumab en sujetos con cáncer de mama HER2+ AR+ metastásico o localmente avanzado
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the efficacy and safety of of Enzalutamide with Trastuzumab in patients with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer
    Estudio para evaluar la eficacia y la seguridad de enzalutamida con trastuzumab en sujetos con cáncer de mama HER2+ AR+ metastásico o localmente avanzado
    A.4.1Sponsor's protocol code number9785-CL-1121
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02091960
    A.5.4Other Identifiers
    Name:INDNumber:113,339
    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 SponsorAstellas Pharma Global Development, Inc.
    B.1.3.4CountryUnited States
    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 supportAstellas Pharma Global Development, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455050
    B.5.5Fax number+31715455501
    B.5.6E-mailcontact@nl.astellas.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Xtandi
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    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.3.4Pharmaceutical form Capsule, soft
    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 INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.2Current sponsor codeMDV3100
    D.3.9.3Other descriptive nameEnzalutamide
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Herceptin
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHerceptin (trastuzumab)
    D.3.4Pharmaceutical form Powder for 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 INNTRASTUZUMAB
    D.3.9.1CAS number 180288-69-1
    D.3.9.4EV Substance CodeSUB12612MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer
    Sujetos con cáncer de mama HER2+ AR+ metastásico o localmente avanzado
    E.1.1.1Medical condition in easily understood language
    Female subjects with metastatic or locally advanced breast cancer
    Sujetos femeninos con cáncer de mama HER2+ AR+ metastásico o localmente avanzado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level PT
    E.1.2Classification code 10065430
    E.1.2Term HER-2 positive breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10027475
    E.1.2Term Metastatic breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10072740
    E.1.2Term Locally advanced breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of enzalutamide with trastuzumab in evaluable subjects with human epidermal growth factor receptor 2 positive (HER2+), androgen receptor positive (AR+) and estrogen receptor negative (ER-)/progesterone receptor negative (PgR-), metastatic or locally advanced breast cancer
    Evaluar la eficacia de enzalutamida con trastuzumab en sujetos evaluables con cáncer de mama metastásico o localmente avanzado con expresión de receptores tipo 2 del factor de crecimiento epidérmico humano (HER2+) y de receptores de andrógenos (AR+), y sin expresión de receptores de estrógenos (ER-) ni de progesterona (PgR-)
    E.2.2Secondary objectives of the trial
    To evaluate the following efficacy measures:
    o Best Overall Response Rate (BORR)
    o Overall Response Rate (ORR) at 24 weeks
    o Progression Free Survival (PFS)
    o Time to Progression (TTP)
    o Duration of Response (DOR)
    o Time to Response (TTR)
    o To evaluate safety and tolerability.
    Evaluar los siguientes criterios de eficacia:
    ? Mejor tasa de respuesta global (MTRG)
    ? Tasa de respuesta global (TRG) a las 24 semanas
    ? Supervivencia sin progresión (SSP)
    ? Tiempo hasta la progresión (THP)
    ? Duración de la respuesta (DR)
    ? Tiempo hasta la respuesta (THR)
    ? Evaluar la eficacia y la tolerabilidad.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent and privacy language as per national
    regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
    2. The subject is a female ? 18 years of age.
    3. The subject has histologically or cytologically proven adenocarcinoma of the breast that is HER2+ defined as a score of 3+ for staining by immunohistochemistry (IHC), or IHC 2+ with
    HER2 gene amplification as determined by a locally approved in situ hybridization (ISH) assay, or (for patients without IHC data) HER2 gene amplification.
    4. The subject has AR+ and ER- /PgR- breast cancer:
    a) AR+ breast cancer is defined as any tumor cells with nuclear AR staining by immunohistochemistry (IHC). Enrollment may be based on the local pathologist?s findings; however, tissue will be sent to a central pathology laboratory for assessment.
    NOTE: If a subject is enrolled in the study based on local pathologist results, but subsequent central assessment cannot confirm AR+ disease, the subject may remain in the study.
    b) ER-/PgR- breast cancer is defined as < 1% of tumor cells with nuclear ER/PgR staining by immunohistochemistry (IHC) or (for subjects with 1 - <10% tumor cells with nuclear
    ER/PgR staining by IHC) the investigator would not treat with hormonal therapy (such as an aromatase inhibitor). Enrollment will be based on the local pathologist?s findings.
    5. The subject has metastatic disease or has locally advanced disease that is not amendable to curative treatment.
    6. The subject has measurable disease according to RECIST 1.1.
    7. The subject has received at least 1 but no more than 4 lines of therapy in the metastatic or locally advanced disease (a line of therapy is defined as a course of treatment at the end of
    which there was disease progression):
    a) The subject has been documented to have progressed by investigator determination on a regimen containing an approved anti-HER2 agent (includes trastuzumab emtansine in
    countries where it is not approved) as the most recent regimen. NOTE: Pertuzumab in the most recent regimen is exclusionary.
    b) The subject progressed on a trastuzumab containing regimen for adjuvant (defined as progression >12 months after completing adjuvant treatment) or metastatic/ locally
    advanced disease.
    The subject has adequately recovered from toxicities due to prior therapy.
    9. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status < 1 at Screening and Day 1.
    10. The subject has available at the site a representative, formalin-fixed, paraffin-embedded, tumor specimen that enabled the definitive diagnosis of breast cancer with adequate viable tumor
    cells in a tissue block (preferred) or ? 10 (20 preferred) freshly cut, unstained, serial slides and the associated pathology report:
    a) Archival tissue from a primary tumor is preferred, but if the specimen is insufficient or unavailable, a core needle or incisional biopsy from a metastatic lesion is acceptable.
    b) Cytological or fine-needle aspiration samples are not acceptable.
    11. The subject has an estimated life expectancy of at least 6 months at Day 1, in the opinion of the Investigator.
    12. The subject is either: Of non-childbearing potential: a) post-menopausal (defined as no spontaneous menses for at least 12 months prior to Screening with FSH > 40 IU/L for women < 55 years of age at Screening),b) documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening),
    Or, if of childbearing potential,
    a) must have a negative urine pregnancy test at Screening and at Day 1 before the first dose of study drug is administered, b) must use 2 acceptable methods of birth control starting at Screening and through 3 months after the final study drug administration.
    The 2 acceptable methods of birth control are as follows or per local guidelines where these require additional description of contraceptive methods:
    a) A barrier method (eg, condom by a male partner) is required;
    AND
    b) One of the following is required: 1).Established use of oral, injected, or implanted hormonal method; 2)Placement of an intrauterine device (IUD) or intrauterine system (IUS);3) Additional barrier method including occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;4)Vasectomy or other surgical castration at least 6 months before Screening.
    13. The subject must not be breastfeeding at Screening or during the study period, and for 3 months after the final study drug administration.
    14. The subject must be able to swallow enzalutamide and comply with study requirements.
    15. The subject agrees not to participate in another interventional study while on treatment.
    Waivers to the inclusion criteria will NOT be allowed.
    1. El sujeto ha otorgado su consentimiento y ha firmado un consentimiento informado escrito y la autorización de uso de información personal aprobados por un Comité ético de la
    investigación clínica (CEIC) conforme a la normativa de cada país (por ejemplo, la Health Insurance Portability and Accountability Act (Ley estadounidense de portabilidad y responsabilidad del seguro médico) [HIPAA] para los centros de EE. UU.) antes de iniciar cualquier procedimiento relacionado con el estudio (incluida la retirada de los medicamentos prohibidos, si procede).
    2. Es una mujer mayor de 18 años.
    3. El sujeto presenta un adenocarcinoma de mama confirmado mediante diagnóstico histológico o citológico y HER2+, definido mediante una puntuación de 3+ en la prueba de tinción inmunohistoquímica (IHQ), o una puntuación de 2+ en la prueba IHQ con amplificación genética del HER2, determinada mediante un ensayo de hibridación in situ (ISH) aprobado localmente, o una amplificación genética del HER2 (para sujetos sin datos de IHQ).
    4. El sujeto tiene cáncer de mama AR+ y ER- /PgR-:? El cáncer de mama AR+ se define como aquel con tinción inmunohistoquímica (IHQ) nuclear positiva para AR. La inclusión podrá basarse en los hallazgos del anatomopatólogo local; no obstante, el tejido se enviará a un laboratorio central de anatomía patológica para su evaluación. NOTA: Si se incluye a un sujeto en el estudio en función de los resultados obtenidos por el anatomopatólogo local, pero la expresión positiva de AR no puede confirmarse en la evaluación posterior efectuada por el laboratorio central, el sujeto podrá permanecer en el estudio.
    ? El cáncer de mama ER-/PgR- se define como aquel con menos del 1 % de células tumorales con tinción inmunohistoquímica (IHQ) nuclear positiva para ER/PgR o bien, para sujetos con un 1 % a menos de un 10 % de células tumorales con tinción inmunohistoquímica nuclear positiva para ER/PgR, que el investigador no trataría con hormonoterapia (como un inhibidor de la aromatasa). La inclusión se basará en los hallazgos del anatomopatólogo local.
    5. El sujeto presenta metástasis o un cáncer localmente avanzado que no puede corregirse mediante un tratamiento curativo.
    6. El sujeto tiene una enfermedad medible según los criterios RECIST 1.1.
    7. El sujeto ha recibido un mínimo de 1 y un máximo de 4 líneas de tratamiento para el cáncer localmente avanzado o metastásico (una línea de tratamiento se define como un ciclo de tratamiento al término del cual ha habido progresión de la enfermedad):
    ? El investigador ha determinado la progresión de la enfermedad del sujeto con un tratamiento que incluya un fármaco anti-HER2 aprobado (incluye trastuzumab emtansina en países donde no está autorizado) en el régimen más reciente. NOTA: La inclusión de pertuzumab en el régimen más reciente es motivo de exclusión.
    ? La enfermedad del sujeto progresó con un régimen terapéutico que incluía trastuzumab como tratamiento para la enfermedad adyuvante (definida como progresión ? 12 meses después de completar el tratamiento adyuvante), metastásica o localmente avanzada.
    8. El sujeto se ha recuperado adecuadamente de la toxicidad derivada de los tratamientos previos.
    9. El sujeto ha obtenido una puntuación de estado funcional del Eastern Cooperative Oncology Group (ECOG) ? 1 en la selección y el día 1.
    10. Existe en el centro una muestra tumoral representativa del sujeto incluida en parafina y fijada con formalina que haya permitido el diagnóstico definitivo del cáncer de mama con células tumorales viables adecuadas en un bloque de tejido (preferible) o ? 10 (20, preferentemente) preparaciones seriadas recién cortadas sin teñir y el informe anatomopatológico correspondiente.
    A)Es preferible emplear tejido de archivo del tumor principal, pero si la muestra es insuficiente o no se dispone de ella, se admite una biopsia por incisión o por punción con aguja gruesa de una lesión metastásica.
    B)No se admiten las muestras citológicas ni de aspiración con aguja fina.
    11. En opinión del investigador, el sujeto tiene una esperanza de vida estimada de al menos 6 meses el día 1.
    12. La paciente:
    ? No puede quedarse embarazada:
    a)Es posmenopáusica (lo que significa que no ha tenido menstruación espontánea durante al menos 12 meses antes de la selección, con valores de FSH > 40 UI/l para mujeres menores de 55 años en el momento de la selección);
    b)Se ha documentado su esterilización quirúrgica o histerectomía (como mínimo 1 mes antes de la selección);
    O bien, si puede quedarse embarazada:
    a)Debe haber obtenido un resultado negativo en una prueba de embarazo en orina realizada en la selección y el día 1, antes de la administración de la primera dosis del fármaco del estudio,
    b)Debe utilizar 2 métodos anticonceptivos aceptables desde el momento de la selección y hasta 3 meses después de la suspensión de la administración del fármaco del estudio.
    Ver Protocolo para otros criterios de inclusión.
    E.4Principal exclusion criteria
    1.The subject has a severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
    2.The subject has current or previously treated brain metastasis or active leptomeningeal disease.Brain imaging is required during screening in all subjects to exclude the presence of unequivocal central nervous system disease.
    3.The subject has a history of a non-breast cancer malignancy with the following exceptions:a)The subject with a previous history of a non-invasive carcinoma is eligible if in the opinion of the Investigator he/she has had successful curative treatment any time prior to Screening.b)For all other malignancies, the subject is eligible if they have undergone potentially curative therapy and they have been considered disease free for at least 5 years prior to Screening.
    4.The subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as: 1)absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3) 2)Platelet count < 75 x109/L (< 75,000 cells/mm3) 3) Hemoglobin < 5.6 mmol/L (< 9 g/dL) 4) Total bilirubin > 1.5 x Upper Limit of Normal (ULN) unless there is an alternate nonmalignant etiology (e.g., Gilbert?s syndrome). 5) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN (or >5 xULN if hepatic metastasis is present).6)Creatinine > 1.5 x ULN. NOTE: May not have received any growth factors or blood transfusions within 7 days before the hematology values obtained at screening
    5.The subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma).
    6.The subject has a history of loss of consciousness, cerebrovascular accident or transient ischemic attack within 12 months before the Day 1 visit.
    7. The subject has had a hypoglycemic episode requiring medical intervention while on insulin (or other anti-diabetic) treatment within 12 months before Day 1.
    8.The subject has clinically significant cardiovascular disease including: a) Myocardial infarction within 6 months before the Day 1 visit. b) Uncontrolled angina within 6 months before the Day 1 visit. c) Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA Class III or IV in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a left ventricular ejection fraction that is ? 50%. d)History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade de Pointes).e) History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. f) Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit. g) Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of < 50 beats per minute on the Screening electrocardiogram (ECG) recording. h) Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit.
    9. The subject has significant respiratory disease, including severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
    10. The subject has an active gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease) within the 3 months prior to the Day 1 visit.
    11. The subject had a major surgical procedure, substantial open biopsy, or significant traumatic experience within 28 days before the Day 1 visit, or anticipation of need for major surgical procedure during the course of the study.
    12. The subject has had palliative radiation therapy to bone metastases within 14 days prior to the Day 1 visit (side effects from radiation must be resolved).
    13. The subject has received chemotherapy, immunotherapy, or any other systemic anti-cancer therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab and trastuzumab emtansine), within 14 days prior to the Day 1 visit.
    14. The subject has been treated with any investigational drugs within 14 days prior to the Day 1 visit.
    15. The subject has received treatment with any approved or investigational agent that either blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, enzalutamide, TAK-448, TAK-683, TAK-700, ARN-509, ODM-201, BMS-641988). Subjects who received treatment for <28 days or placebo on an investigational study are acceptable.
    16. The subject has received pertuzumab in the most recent line of therapy.
    17. The subject has used any of the following within 28 days before the Day 1 visit: - 5-? reductase inhibitors -
    For other exclusion criteria see protocol.
    Waivers to the exclusion criteria will NOT be allowed
    1. El sujeto presenta una comorbilidad, enfermedad o infección graves concomitantes que, en opinión del investigador, lo convierten en no apto para su inclusión en el estudio.
    2. El sujeto tiene una metástasis intracraneal presente o previamente tratada, o enfermedad leptomeníngea activa. Durante la selección, todos los sujetos deben someterse a un diagnóstico por imágenes cerebrales para descartar la presencia de una enfermedad inequívoca del sistema nervioso central.
    3. El sujeto tiene antecedentes de neoplasias malignas distintas al cáncer de mama, con las siguientes excepciones:a)Los sujetos con antecedentes de carcinoma no invasivo podrán participar en el estudio si, en opinión del investigador, se han sometido con éxito a tratamientos curativos en algún momento antes de la selección.b)Para el resto de neoplasias malignas, los sujetos podrán participar si se han sometido a tratamientos potencialmente curativos y se ha considerado que estaban libres de enfermedad durante al menos 5 años antes de la selección.
    4. La función renal, hepática o de la médula ósea del sujeto es inadecuada en la visita de selección; la función inadecuada se define como:1)Recuento absoluto de neutrófilos < 1,5 x109/l (< 1500 células/mm3) 2)Recuento absoluto de plaquetas < 75 x109/l (< 75 000 células/mm3) 3)Hemoglobina < 5,6 mmol/l (< 9 g/dl) 4)Bilirrubina total > 1,5 veces el límite superior de la normalidad (LSN) salvo en el caso de que las causas no sean atribuibles al cáncer (p. ej. síndrome de Gilbert). 5)Aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) > 3 veces el límite superior de la normalidad (o > 5 veces el límite superior de la normalidad si hay metástasis hepática).6)Creatinina > 1,5 veces el límite superior de la normalidad. NOTA: Los sujetos no deben haber recibido factores de crecimiento o transfusiones sanguíneas en el plazo de 7 días antes de la obtención de los valores hematológicos en la selección.
    5. El sujeto tiene antecedentes de convulsiones o de algún trastorno que pueda predisponerle a sufrir convulsiones (p. ej. ha sufrido un ictus cortical o un traumatismo intracraneal importante).
    6. El sujeto tiene antecedentes de pérdida de conciencia, accidente vascular cerebral o crisis isquémica transitoria en los 12 meses anteriores a la visita del día 1.
    7. El sujeto ha tenido un episodio hipoglucémico que ha precisado intervención médica mientras estaba siendo tratado con insulina (u otro fármaco contra la diabetes) en los 12 meses anteriores a la visita del día 1.
    8. El sujeto presenta una enfermedad cardiovascular clínicamente importante, como: a)Infarto de miocardio en los 6 meses anteriores a la visita del día 1.b)Angina de pecho no controlada en los 6 meses anteriores a la visita del día 1.c)Insuficiencia cardíaca congestiva de clase III o IV según la clasificación de la New York Heart Association (NYHA), o antecedentes de insuficiencia cardíaca congestiva de clase III o IV según la NYHA, salvo que un ecocardiograma en la selección o una ventriculografía nuclear (MUGA) realizados en el plazo de 3 meses antes de la visita del día 1 muestren una fracción de eyección del ventrículo izquierdo ? 50 %;
    d)Antecedentes de arritmias ventriculares clínicamente significativas (p. ej. taquicardia ventricular, fibrilación ventricular, torsade de pointes);
    e)Antecedentes de bloqueo auriculoventricular de Mobitz II de segundo o tercer grado en sujetos sin marcapasos permanentes;
    f)Hipotensión, indicada por una presión arterial sistólica < 86 mm Hg en 2 determinaciones consecutivas en la visita de selección.g)Bradicardia (en presencia de enfermedad cardiovascular conocida) indicada por una frecuencia cardíaca inferior a 50 latidos por minuto en el ECG de la selección.
    h)Hipertensión no controlada, indicada por una presión arterial sistólica > 170 mm Hg o una presión arterial diastólica > 105 mm Hg en dos determinaciones consecutivas en la visita de selección.
    9. El sujeto presenta una enfermedad respiratoria significativa con disnea intensa en reposo debido a complicaciones de un cáncer avanzado o que requiera oxigenoterapia complementaria.
    10. El sujeto presenta un trastorno gastrointestinal activo que afecta a la absorción (p. ej. gastrectomía, úlcera péptica activa) en los 3 meses anteriores a la visita del día 1.
    11. El sujeto se ha sometido a una intervención quirúrgica importante, a una biopsia abierta sustancial o a una experiencia traumática significativa en los 28 días anteriores a la visita del día 1, o se prevé que sea necesario someterlo a una intervención quirúrgica importante durante el transcurso del estudio.
    12. El sujeto ha recibido radioterapia paliativa para la metástasis ósea en los 14 días anteriores a la visita del día 1 (deben haberse resuelto los efectos secundarios de la radiación).
    Ver Protocolo para otros criterios de exclusión.
    NO se permitirán excepciones a los criterios de exclusión.
    E.5 End points
    E.5.1Primary end point(s)
    CBR defined as the proportion of subjects with best objective response of CR, PR or SD at ? 24 weeks according to RECIST 1.1 criteria.
    Tasa de beneficio clínico (TBC), definida como la proporción de sujetos con mejor respuesta objetiva de RC, RP o EE a las 24 semanas o más, según los criterios RECIST 1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to 2 years
    durante un máximo de 2 años
    E.5.2Secondary end point(s)
    Overall response rate (CR+PR) according to RECIST 1.1 criteria
    Tasa de respuesta global (TRG: RC + RP) según los criterios RECIST 1.1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to 2 years
    durante un máximo de 2 años
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 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 concerned24
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA24
    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
    Belgium
    Canada
    Ireland
    Italy
    Russian Federation
    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
    LSLV
    Última visita del último sujeto
    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 months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months7
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 80
    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)
    Plans for treatment or care after for the subject is per the treating physician's discretion and what is best for the subject.
    Los planes de tratamiento o la atención para el sujeto se realizarán según jucio del médico y lo que sea mejor para el sujeto.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation ICORG
    G.4.3.4Network Country Ireland
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2014-06-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-18
    P. End of Trial
    P.End of Trial StatusCompleted
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