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    Summary
    EudraCT Number:2014-004072-30
    Sponsor's Protocol Code Number:GETNE-1408
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-12-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-004072-30
    A.3Full title of the trial
    A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) previously untreated
    Estudio fase II para evaluar la actividad y seguridad de TH-302 en combinación con sunitinib para pacientes con tumores neuroendocrinos pancreáticos (pNET) bien o moderadamente diferenciados metastásicos no tratados previamente.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II trial to assess the activity and safety of TH-302 in combination with sunitinib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) previously untreated
    Estudio fase II para evaluar la actividad y seguridad de TH-302 en combinación con sunitinib para pacientes con tumores neuroendocrinos pancreáticos (pNET) bien o moderadamente diferenciados metastásicos no tratados previamente.
    A.3.2Name or abbreviated title of the trial where available
    SUNINET
    A.4.1Sponsor's protocol code numberGETNE-1408
    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 SponsorGrupo Español de Tumores Neuroendocrinos
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMFAR, S.L.
    B.5.2Functional name of contact pointFederico Nepote
    B.5.3 Address:
    B.5.3.1Street AddressSecretari Coloma 64-68. esc B entlo 5ª
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08024
    B.5.3.4CountrySpain
    B.5.4Telephone number+34934344412
    B.5.5Fax number+34932531168
    B.5.6E-mailinvestigacion@mfar.net
    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 Sutent
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer, Ltd., Sandwich - Kent, United Kingdom
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSUNITINIB
    D.3.9.1CAS number 557795-19-4
    D.3.9.2Current sponsor codePR-1
    D.3.9.4EV Substance CodeSUB22321
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSUNITINIB
    D.3.9.1CAS number 557795-19-4
    D.3.9.2Current sponsor codePR-1
    D.3.9.4EV Substance CodeSUB22321
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 nameTH-302
    D.3.2Product code TH-302
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot Available
    D.3.9.2Current sponsor codePR-2
    D.3.9.3Other descriptive nameTH-302
    D.3.9.4EV Substance CodeSUB120849
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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
    Patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumours (pNET).
    Pacientes con tumores neuroendocrinos pancreáticos (pNET) bien o moderadamente diferenciados metastásicos.
    E.1.1.1Medical condition in easily understood language
    Metastatic pancreatic tumours
    Tumores pancreáticos metastásicos
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Objective Response Rate (OOR)
    Tasa de respuestas objetivas (TRO).
    E.2.2Secondary objectives of the trial
    Progression Free Survival (PFS)
    Time to Tumour Progression (TTP)
    Duration of Response (DR)
    Overall Survival (OR)
    Safety
    Biomarkers in serum and tumor tissue
    Supervivencia libre de progresión (SLP)
    Tiempo hasta la progresión (TTP)
    Duración de la respuesta (DR)
    Supervivencia global (SG)
    Seguridad
    Biomarcadores serológicos y en tejido tumoral
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Biomarkers in serum and tumor tissue. The sub-study is enclosed in the protocol.

    Objectives:

    - To asses the correlation between radiological response and clinical evolution of the patient and the expression level of:
    - ENO1 (enolasa 1) in plasma
    - SNPs (single nucleotide polymorphisms) related with the activity and metabolism of sunitinib and TH-302s VEGFR2 (rs2305948 y rs1870377), VEGFR3 (rs307826), IL8 (rs1126647), CYP3A4 (rs35599367 y rs67666821), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503 y rs2032582), POR (rs1057868 y c.1705_1706insG). Te inclusion of a new polymorphism with special relevance and related to the efficacy of sunitinib or TH-302 will be considered during the study
    - Hypoxia related markers related with the tumour in tumor tissue included in paraffin (HIF1- ?, CYP2W1 and c-Myc).
    Se evalúa la correlación entre la respuesta radiológica y evolución clínica del paciente
    y los niveles de expresión de:
    - ENO1 (enolasa 1) en plasma (será realizado localmente en los mismos plazos
    que cromogranina en cada centro participante)
    - SNPs (single nucleotide polymorphisms) relacionados con la actividad y
    metabolismo del sunitinib y TH-302s VEGFR2 (rs2305948 y rs1870377),
    VEGFR3 (rs307826), IL8 (rs1126647), CYP3A4 (rs35599367 y rs67666821),
    CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503 y rs2032582), POR
    (rs1057868 y c.1705_1706insG). Si a lo largo del estudio apareciese en la
    literatura un polimorfismo de especial relevancia y relacionado con la eficacia
    del sunitinib o TH-302, podría considerarse su inclusión en el estudio.
    - Marcadores de hipoxia relacionada con el tumor en tejido tumoral parafinado
    (HIF1- ?, CYP2W1 and c-Myc).
    E.3Principal inclusion criteria
    1. Male or female, 18 years of age or older.
    2. ECOG performance status 0-1.
    3. Histologically proven diagnosis of pancreatic neuroendocrine tumors (pNET) with Ki67 assessment of < or = 20% (well and moderately differentiated)
    4. Evidence of unresectable disease or metastatic disease. Locally advanced disease must not be amendable to resection or radiation therapy with curative intent.
    5. Patients may be treated with somatostatin analogues prior or during the trial. Concomitant or prior interferon treatment is not permitted.
    6. Documented progression disease by CT scan, MR or Octreoscan in 12 months prior basal visit.
    7. Measurable disease as per RECIST. Measurable lesions that have been previously radiated will not be considered target lesions unless increase in size has been observed following completion of radiation therapy.
    8. Patient has to be able to swallow the medication.
    9. Life expectancy greater than 12 weeks.
    10. The definitions of minimum adequacy for organ function required prior to study entry are as follows.
    Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ? 2.5 x upper limit of normal (ULN), or AST and ALT ? 5 x ULN if liver function abnormalities are due to underlying malignancy
    Total serum bilirubin ? 1.5 x ULN
    Serum albumin ? 3.0 g/dL
    Absolute neutrophil count (ANC) ? 1500/µL
    Platelets ?100,000/µL
    Hemoglobin ? 5,6 mmol/L (9.0 g/dL)
    Creatinin clearance > 40 mL/min (Cockroft and Gault formula)
    11. Adequate cardiac function: 12-lead ECG without pathologic findings (clinically significant alterations are allowed) and Echocardiogram / Normal MUGA (LVEF> 50%)
    12. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
    13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
    1 Edad ?18 años capaces de otorgar su consentimiento informado.
    2 Estado funcional ECOG (Eastern Cooperative Oncology Group) 0 ó 1
    3 Tumores neuroendocrinos pancreáticos (pNET) diagnosticado histológicamente con un Ki67 ? 20% (tumores bien o moderadamente diferenciados).
    4 Evidencia de enfermedad irresecable o metastásica. Si se trata de una enfermedad localmente avanzada, no será susceptible de resección quirúrgica o tratamiento radioterápico con intención curativa.
    5 No será permitido el tratamiento sistémico previo. Los pacientes pueden haber recibido tratamiento previo o concomitante con ASS. No se permitirá el tratamiento previo o concomitante con interferón (IFN).
    6 Progresión tumoral documentada por TC, RM u Octreoscán en los 12 meses previos a la visita basal.
    7 Enfermedad medible por criterios RECIST 1.1. Las lesiones medibles que hayan sido previamente radiadas no serán consideradas como lesiones diana a no ser que el incremento de tamaño se haya observado tras la finalización de dicho tratamiento.
    8 El paciente deberá ser capaz de ingerir la medicación vía oral.
    9 Esperanza de vida superior a 12 semanas.
    10 Se requieren los siguientes valores analíticos correspondientes a una adecuada función orgánica y de la médula ósea.
    Aspartato aminotransferasa (AST) y Alanina aminotransferasa (ALT) ?2.5 veces por el límite superior de la normalidad (LSN), o AST y ALT ?5 x LSN si la alteración en la función hepática es secundaria a enfermedad tumoral subyacente.
    Bilirrubina sérica total ?1.5 x LSN
    Albúmina sérica ?3.0 g/dL
    Recuento absoluto de neutrófilos ?1500/µL.
    Plaquetas ? 100 000/µL
    Hemoglobina ? 5,6 mmol/L (9 g/dL)
    Aclaramiento de creatinina > 40 mL/min (Fórmula Cockroft and Gault)
    11. Función cardíaca adecuada:
    ECG de 12 derivaciones sin hallazgos patológicos (se permiten alteraciones clínicamente no significativas)
    Ecocardiograma/MUGA normal (FEVI > 50%)
    12. Consentimiento informado con fecha y firma indicando que el paciente (o el representante aceptado legalmente) ha sido informado sobre todos los aspectos pertenecientes al estudio previamente a su inclusión.
    13. El paciente deberá ser capaz de cumplir con las visitas requeridas por el estudio, el tratamiento, los análisis de laboratorio y otros procedimientos del estudio.
    E.4Principal exclusion criteria
    1. Previous treatments with chemotherapy, monoclonal antibodies anti-VEGF, tyrosine kinase inhibitors, mTOR inhibitors, or interferon are not permitted for the advanced disease.
    2. Prior treatment on another hypoxia-activated prodrug under clinical trial.
    3. Major surgery, radiation therapy, or systemic therapy within 3 weeks of study randomization except palliative radiotherapy to non-target metastatic lesions.
    4. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
    5. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids taken concurrently or within last 3 months prior to randomization
    6. Treatment with known inhibitors or inductors of CYP3A4 or that prolong the QT interval in the previous 7 days.
    7. Prior radiation therapy to >25% of the bone marrow.
    8. Current treatment on another clinical trial.
    9. Uncontrolled brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. Patients should have completed surgery or radiation therapy for existing brain metastases, should not have documented increase in size over the previous 3 months prior to first dose of treatment on study and should be asymptomatic.
    10. Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
    11. Any of the following within the 12 months prior to starting study treatment:
    - myocardial infarction,
    - severe/unstable angina,
    - coronary/peripheral artery bypass graft,
    - congestive heart failure class III or IV of the New York Heart Association (NYHA) or patients with clinical history of congestive heart failure clase III or IV of the NYHA, unless an echocardiogram or MUGA in the pevious 3 months to selection shows a LVEF ? 45 %
    - significant heart valve disease
    - cerebrovascular accident including transient ischemic attack
    - pulmonary embolus.
    12. Ongoing cardiac dysrhythmias of NCI CTCAE grade ? 2, atrial fibrillation of any grade, or QTc interval >450 msec for males or >470 msec for females.
    13. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
    14. Chronic obstructive pulmonary disease (COPD) or any other disease concurrent with hypoxemia or oxigen saturation < 90% after a march of two minutes.
    15. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
    16. Known human immunodeficiency virus infection.
    17. Pregnancy or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to inclusion.
    18. Previous allergic reaction to components structurally similar to TH-302 or sunitinib or any of the excipients of drugs.
    19. Non-healing wound, fistulae, active peptic ulcer or bone fracture.
    20. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    1. Tratamiento previo con quimioterapia, anticuerpos monoclonales frente al VEGF, inhibidores de tirosinkinasa (ITK), inhibidores de mTOR, quimioterapia o interferón (IFN) administrados para la enfermedad avanzada.
    2. Tratamiento previo con otro fármaco activado por hipoxia bajo ensayo clínico.
    3. Cirugía mayor, radioterapia o tratamiento sistémico en las 4 semanas previas a la inclusión en el estudio, excepto en el caso del tratamiento radioterápico paliativo sobre lesiones metastásicas no diana.
    4. Tratamiento previo con quimioterapia a altas dosis que haya requerido soporte hematopoyético de rescate.
    5. Tratamiento inmunosupresor como ciclosporina, tacrolimus, azatioprina o tratamiento prolongado con corticoides administrados de forma concomitante o en los 3 meses previos a la inclusión en el estudio.
    6. Tratamiento, dentro de los 7 días previos a la inclusión en el estudio de fármacos inhibidores o inductores potentes conocidos de CYP3A4 o que prolongan el intervalo QT.
    7. Tratamiento radioterápico previo sobre >25% de la médula ósea.
    8. Tratamiento dentro de otro ensayo clínico.
    9. Presencia de enfermedad metastásica cerebral no controlada, compresión medular, carcinomatosis meníngea o enfermedad leptomeníngea. Los pacientes deberán haber completado la cirugía o radioterapia para las lesiones cerebrales preexistentes, sin documentarse un incremento en el tamaño de las mismas en los tres meses previos a la primera dosis del tratamiento del estudio y deben ser asintomáticas.
    10. Diagnóstico de una segunda neoplasia en los últimos 3 años, excepto tumores cutáneos escamosos o basaliomas adecuadamente tratados o carcinomas in situ de cérvix.
    11. Enfermedad cardio/cerebrovascular clínicamente significativa en los 12 meses previos al inicio del tratamiento, que incluye:
    Infarto de miocardio
    Angina severa/inestable
    Implantación de bypass en arteria periférica o coronaria
    Insuficiencia cardiaca congestiva clase III o IV de la New York Heart Association (NYHA) o pacientes con historia de insuficiencia cardiaca congestiva clase III o IV de la NYHA, a no ser que un ecocardiograma o MUGA en los 3 meses previos a la selección muestre una fracción de eyección del ventrículo izquierdo ?45 %.
    Valvulopatía cardíaca significativa.
    Accidente cerebrovascular que incluya accidente isquémico transitorio.
    Tromboembolismo pulmonar.
    12. Arritmias cardíacas (NCI CTCAE versión 4.0 grado ?2), fibrilación auricular de cualquier grado o intervalo QTc >450 mseg para varones o >470 mseg para mujeres.
    13. Hipertensión mal controlada a pesar del tratamiento óptimo (>150/100 mmHg)
    14. Enfermedad pulmonar obstructiva severa (EPOC) o cualquier enfermedad pulmonar que curse con hipoxemia o saturación de oxígeno < 90% tras una marcha de 2 minutos.
    15. Tratamiento actual con coumadin a dosis terapéuticas (se permitirá la administración de bajas dosis de coumadin hasta 2mg/24h para profilaxis de trombosis venosa profunda).
    16. Infección conocida del virus de la inmunodeficiencia humana (VIH).
    17. Embarazo o lactancia. Todas aquellas mujeres en edad fértil deberán presentar un test de embarazo negativo (sangre u orina) de forma previa a la inclusión en el estudio.
    18. Reacción alérgica previa a componentes estructuralmente similares a TH-302 o sunitinib o a alguno de los excipientes de los fármacos.
    19. Herida que no cicatriza, fístulas, úlcera péptica activa o fracturas óseas.
    20. Cualquier enfermedad (médica o psiquiátrica) o motivo que, en opinión del investigador, interfiera con la capacidad del paciente para participar en el ensayo clínico, colocando al paciente en una situación de riesgo excesivo o complicando la interpretación de los datos de seguridad y siendo inapropiado para la inclusión en el estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Objective response rate: percentage of patients in whom a complete response (CR) or a partial response (PR) is confirmed according RECIST criteria in relation to the total of the analysed population.
    La tasa de respuestas objetivas correspondiente al porcentaje de pacientes en los que se confirma una respuesta completa (RC) o una respuesta parcial (RP) según criterios RECIST, en relación al total de la población analizada.
    E.5.1.1Timepoint(s) of evaluation of this end point
    the objective response rate will be assessed according to RECIST criteria which will be held every 8 weeks, regardless of delays in the secondary treatment toxicity.
    Se evaluará según los criterios RECIST v 1.1 que se llevarán a cabo cada 8 semanas, independientemente de los retrasos en el tratamiento secndarios a toxicidad del tratamiento.
    E.5.2Secondary end point(s)
    Progression Free Survival (PFS) - Time between the start of study treatment to date of the first objective evidence of radiological progression or patient death due to any cause; which comes first.
    Time to Tumour Progression (TTP) - It is defined as the time between the start of study treatment to date of the first objective evidence of radiological progression.
    Duration of Response (DR) - It is defined as the time between the start from the first documentation of objective response (CR or PR) which is subsequently confirmed until the first objective evidence of radiological progression or death from any cause.
    DR is calculated only in the subgroup of patients with an objective response (CR + PR).
    Overall Survival (OR) - It is defined as the time between the start of study treatment to date of death from any cause. If it were impossible to obtain confirmation of the death, survival will be censored with the date of the last visit that it is satisfied that the patient was alive.
    Safety - The safety period includes the time between the date of signing the informed consent until 28 days after the last dose of study drug. Safety will be assessed according to the reports of adverse events, the frequency of treatment discontinuations due to adverse events, laboratory evaluations or ECG
    Biomarkers in serum and tumor tissue ? See sub-study
    Supervivencia libre de progresión (SLP) - Se define como el tiempo entre el inicio del tratamiento de estudio hasta la fecha de la primera evidencia objetiva de progresión radiológica o fallecimiento del paciente debido a cualquier causa; la que suceda primero.
    Tiempo hasta la progresión (TTP) - Se define como el tiempo entre el inicio del tratamiento del estudio hasta la fecha de la primera evidencia objetiva de progresión radiológica.
    Duración de la respuesta (DR) - Se define como el tiempo entre el inicio desde la primera documentación de respuesta objetiva (RC o RP) que es posteriormente confirmada, hasta la primera evidencia objetiva de progresión radiológica o fallecimiento por cualquier causa. DR se calculará únicamente en el subgrupo de pacientes con respuesta objetiva (RC + RP).
    Supervivencia global (SG) - Se define como el tiempo entre el inicio del tratamiento del estudio hasta la fecha de fallecimiento por cualquier causa.
    Si no fuera posible obtener la confirmación del fallecimiento, la supervivencia será censurada con la fecha de la última visita de la que se tenga constancia que el paciente estaba vivo.
    Seguridad - El período de seguridad comprende entre la fecha de la firma del consentimiento informado hasta 28 días después de la última dosis del fármaco de estudio. La seguridad se evaluará según los reportes de acontecimientos adversos, la frecuencia de interrupciones del tratamiento por eventos adversos, las valoraciones analíticas o de los ECG. Se utilizará un análisis descriptivo.
    Biomarcadores en suero y en tejido tumoral - Ver subestudio
    E.5.2.1Timepoint(s) of evaluation of this end point
    Progression Free Survival (PFS) - duration of the trial
    Time to Tumour Progression (TTP) - duration of the trial
    Duration of Response (DR) - duration of the trial
    Overall Survival (OR) - duration of the trial
    Safety - The safety period includes the time between the date of signing the informed consent until 28 days after the last dose of study drug
    Biomarkers in serum and tumor tissue - see sub-study
    Supervivencia libre de progresión (SLP) - Durante todo el ensayo
    Tiempo hasta la progresión (TTP) - Durante todo el ensayo
    Duración de la respuesta (DR) - Durante todo el ensayo
    Supervivencia global (SG) - Durante todo el ensayo
    Seguridad - El período de seguridad comprende entre la fecha de la firma del consentimiento informado hasta 28 días después de la última dosis del fármaco de estudio.
    Biomarcadores en suero y en tejido tumoral - Ver subestudio
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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.8.3 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 concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    October 2017
    Octubre 2017
    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 months2
    E.8.9.1In the Member State concerned days
    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: 43
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 43
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state43
    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)
    Expected normal treatment for the pathology
    Tratamiento habitual previsto para la patología
    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 Decision2015-01-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-12
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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