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    EudraCT Number:2014-004848-36
    Sponsor's Protocol Code Number:BAY80-6946/17119
    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:2015-04-27
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-004848-36
    A.3Full title of the trial
    An open-label, single-arm Phase II study in patients with relapsed or
    refractory diffuse large B-cell lymphoma (DLBCL) to evaluate efficacy and
    safety of treatment with single agent copanlisib and the impact of
    biomarkers thereupon.
    Estudio abierto, de un solo brazo, Fase II, en pacientes con linfoma difuso de células B (DLBCL) en recaída o refractarios para evaluar la eficacia y seguridad de copanlisib en monoterapia y el impacto de los biomarcadores sobre estos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to investigate the efficacy and safety of copanlisib in
    patients with relapsed or refractory diffuse large B-cell lymphoma.
    Estudio para evaluar la eficacia y seguridad de copanlisib en pacientes con linfoma difuso de celulas B en recaída o refractarios
    A.3.2Name or abbreviated title of the trial where available
    Phase II copanlisib in relapsed/refractory DLBCL
    Fase II de Copanlisib en DLBCL en recaída o refractarios
    A.4.1Sponsor's protocol code numberBAY80-6946/17119
    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 SponsorBayer HealthCare AG
    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 supportBayer HealthCare AG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBayer HealthCare AG
    B.5.2Functional name of contact pointBayer Clin. Trials Contact CTP Team
    B.5.3 Address:
    B.5.3.1Street AddressBayer Pharma AG, S102, Level 2, Room 156
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13342
    B.5.4Telephone number0034.900102372
    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 nameCopanlisib
    D.3.2Product code BAY84- 1236
    D.3.4Pharmaceutical form Lyophilisate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCopanlisib
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.3Other descriptive nameBAY 80-6946 (AS DIHYDROCHLORIDE BAY 84-1236)
    D.3.9.4EV Substance CodeSUB32033
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 relapsed or refractory diffuse large B cell lymphoma
    pacientes con linfoma difuso de celulas B en recaída o refractarios
    E.1.1.1Medical condition in easily understood language
    patients with relapsed or refractory diffuse large B cell lymphoma
    pacientes con linfoma difuso de celulas B en recaída o refractarios
    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
    The primary objective of this study is to assess the potential efficacy (in terms of objective response) of single agent copanlisib in patients with relapsed or refractory DLBCL and assess the relationship between efficacy and a potentially predictive biomarker.
    El objetivo principal del estudio es evaluar la potencial eficacia (en términos de respuesta objetiva) de copanlisib en monoterapia en pacientes con DLBCL en recaída o refractarios al tratamiento y evaluar la relación entre la eficacia y un posible biomarcador predictivo.
    E.2.2Secondary objectives of the trial
    Secondary objectives of this study are to assess:
    - Other radiological and survival indicators of treatment efficacy.
    - Safety and tolerability of copanlisib
    - Long-term effects of the treatment

    Further objectives of this study are to assess:
    -Pharmacokinetics of copanlisib
    - To explore additional biomarkers in predicting efficacy
    - Patient-reported outcomes
    Los objetivos secundarios de este estudio son evaluar:
    - Otros indicadores radiológicos y de supervivencia de la eficacia del tratamiento.
    - Seguridad y tolerabilidad de copanlisib.
    - Efectos a largo plazo del tratamiento.

    Otros objetivos de este estudio son:
    - Evaluar la farmacocinética de copanlisib.
    - Explorar biomarcadores adicionales para el pronóstico de la eficacia.
    - Evaluar los resultados reportados por el paciente
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Ability to understand and willingness to sign written informed consent. Signed informed consent (including consent to genetic analysis) must be obtained before any study specific procedure .
    2.Male or female patients age >= 18 years old
    3.Diagnosis of DLBCL (de novo or DLBCL transformed from follicular lymphoma on the basis of a tissue biopsy). Pathology and immunohistochemistry reports documenting the current histological diagnosis of DLBCL or DLBCL transformed from follicular lymphoma according to WHO classification must be reviewed by the sponsor or designee prior to enrollment. Patients whose NHL has transformed from follicular lymphoma must have had a complete or partial response to first-line therapy for NHL lasting at least 12 weeks.
    - DLBCL not otherwise specified (NOS)
    - T-cell/histiocyte-rich large B-cell lymphoma
    - Epstein-Barr virus (EBV) positive DLBCL of the elderly
    4.Received at least one prior therapy for aggressive NHL (DLBCL)
    Note: High dose myeloablative therapy with SCT used to consolidate a response and local consolidative radiation, corticosteroids as single agents, and maintenance therapy with rituximab or other agents are not considered independent regimens.
    5.Received CHOP + rituximab or equivalent regimen (addition of etoposide or substitution of idarubicin, epirubicin, or mitoxantrone for doxorubicin is allowed) for NHL
    6.At least 28 days from completion of last NHL therapy to first dose of study treatment.
    7.Patients must have measurable disease (at least one bidimensionally measurable site of disease that has not been previously irradiated: nodal disease >1.5 cm or an extranodal lesion > 1.0 cm in longest perpendicular diameter). Lesion must be PET-positive if a PET scan is obtained.
    8.Not eligible or not willing to receive the high-dose (myeloablative) chemotherapy (HDC) and SCT.
    9.A fresh tumor biopsy collected during screening and /or archival tumor tissue collected after the last relapse/disease progression (material which has been collected before the last line of treatment is not accepted). In addition, a sufficient amount of the material is required for acceptance of the archival material. If neither condition occurs a fresh tumor biopsy needs to be performed as stated above.
    10.ECOG performance status (PS) <= 2
    11.Life expectancy >= 12 weeks in investigator's judgment
    12.Left ventricular ejection fraction (LVEF) >= the lower limit of normal (LLN) for the Institution (as per local standard of care) as measured by ECHO (echocardiogram) or Multiple gated acquisition (MUGA) scan
    13.Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before start of study treatment:
    - Hemoglobin >= 8 g/dL
    - Platelet count >= 100 x 109L/; platelet count >= 75 x 109/L permitted if documented bone marrow involvement
    - Absolute neutrophil count (ANC) >= 1.5 x 109/L; ANC >= 1.0 x 109/L permitted if documented bone marrow involvement
    - Total bilirubin <= 1.5 x upper limit of normal (ULN); patients with proven Gilbert's syndrome and total bilirubin <= 5 x ULN may be enrolled.
    - Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <= 2 x ULN, or <= 5 x ULN if elevation is due to hepatic involvement by lymphoma
    - Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (See Appendix 16.4) .
    - International normalized ratio (INR) and partial thromboplastin time (PTT) <= 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring is recommended according to the local standard of care.
    - Lipase < 1.5 x the ULN
    14.Willingness and ability to comply with the visit schedule and assessments required by the study protocol
    15.Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the ICF and 3 months after the last administration of study drug. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
    1.Pacientes capaces de comprender el consentimiento informado(CI)por escrito y estar dispuestos a firmarlo.Deberá obtenerse el CI firmado(incluyendo el CI para los análisis genéticos)antes de los procedimientos específicos del estudio.2.Pacientes varones o mujeres >18 años de edad.3.Diagnóstico de DLBCL(de novo o DLBCL desarollado a partir de linfoma folicular según una biopsia de tejido). Deberán ser revisados por el promotor o quien fuera designado antes de la inclusión los Informes de patología e inmunohistoquímica que documenten el diagnóstico histológico actual de DLBCL o DLBCL transformado de linfoma folicular,según la clasificación de la OMS.Los pacientes cuyo NHL se ha transformado desde linfoma folicular deben haber tenido una respuesta completa o parcial al tratamiento de primera línea para el NHL de al menos 12semanas.?DLBCL no especificado (NOS,siglas en inglés).?Linfoma de células B rico en células T/histiocitos.?DLBCL personas mayores con virus de Epstein-Barr (EBV)positivo.4.Haber recibido al menos un tratamiento previo para el linfoma no Hodgkin agresivo (NHL)(DLBCL ).
    Nota: no son considerados regímenes independientes las dosis altas de la terapia mieloablativa con SCT utilizada para consolidar una respuesta y la radiación de consolidación locales, corticosteroides como agentes únicos, y la terapia de mantenimiento con rituximab u otros agentes. 5.Haber recibido CHOP+rituximab o un régimen equivalente para la NHL(Se permite la adición de etopósido o sustitución de idarubicina,epirubicina,o mitoxantrona por doxorrubicina).6.Al menos 28 días desde la finalización de la última terapia de NHL hasta la primera dosis del tratamiento del estudio.7.Los pacientes deben tener enfermedad medible(al menos un sitio bidimensionalmente medible de la enfermedad que no haya sido previamente irradiado: enfermedad nodal >1,5 cm o una lesión extranodal>1,0 cm en el diámetro perpendicular más largo). La lesión debe ser PET-positivo si se obtiene una tomografía PET.8.No elegible o no está dispuesto a recibir dosis altas (mieloablativa) de quimioterapia (HDC) y SCT.9.Una biopsia tumoral fresca recogida durante la selección y/o tejido tumoral de archivo recogido después de la última recaída/progresión de la enfermedad (no se acepta material que haya sido recogido antes de la última línea de tratamiento). Se requiere una cantidad suficiente de material para la aceptación del material de archivo. Si se produce alguna de estas condiciones se deberá realizar una biopsia de tumor fresco, como se ha indicado anteriormente.10.Estado funcional ECOG (PS) ? 2.11.Esperanza de vida ?12 semanas según el criterio del investigador.12.Fracción de eyección ventricular (FEVI) ? al límite inferior de la normalidad (LIN) utilizado en el centro (conforme se defina en el procedimiento local), medido por un ECHO (ecocardiograma) o una ventriculografía isotópica (MUGA).13.Adecuada función de médula ósea, hígado y renal según la evaluación de los siguientes requisitos de laboratorio llevados a cabo dentro de los 7 días antes del inicio del tratamiento del estudio:Hemoglobina> = 8 g / dl;Recuento de plaquetas> = 100 x 109 L /; recuento de plaquetas >= 75 x 109 / L permitido si hay afectación de médula ósea documentada;Recuento absoluto de neutrófilos (RAN)> = 1.5 x 109 / L; RAN> = 1.0 x 109 / L permitido si hay afectación de médula ósea documentada;Bilirrubina total <= 1,5 veces el límite superior de la normalidad (LSN); los pacientes con síndrome de Gilbert confirmado y bilirrubina total <= 5 x LSN pueden ser incluidos.Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) <= 2 x LSN, o <= 5 x LSN si la elevación se debe a la afectación hepática por el linfoma;Tasa de filtración glomerular (TFG)> = 30 ml / min / 1,73 m2 según la Modificación de la Dieta en la Enfermedad Renal (MDRD) fórmula abreviada (Véase el Apéndice 16.4).Ratio Internacional Normalizado (INR, siglas en inglés) y el tiempo de tromboplastina parcial (TTP) <= 1,5 x LSN. Se permite la participación de pacientes que estén terapéuticamente tratados con agentes como warfarina o heparina siempre que no existan indicios previos de anomalías subyacentes de los parámetros de coagulación. Se recomienda una estrecha monitorización conforme se defina en el procedimiento local.
    14.Estar dispuestos y tener la capacidad de cumplir con el calendario de visitas y evaluaciones requeridos por el protocolo del estudio.15.Las mujeres y los hombres fértiles incluidos en este ensayo deberán aceptar el uso de métodos anticonceptivos adecuados si están sexualmente activos. Esto aplica desde la firma del CI hasta 3 meses después de la última administración del tratamiento del estudio. El investigador o el personal designado deberá asesorar al paciente la forma de lograr un control adecuado. En este ensayo, un método anticonceptivo adecuado se define como cualquier método recomendado desde el punto de vista médico (o combinación de métodos), según las normas asistenciales.
    E.4Principal exclusion criteria
    1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
    2. Concurrent participation in other clinical studies. Patients must complete their participation in another clinical study with an investigational medicinal product 28 days before the start of treatment or 5 half-lives of the investigational treatment, whichever is longer.
    3. Patients who previously received therapy with copanlisib or other PI3K inhibitors are not eligible for enrollment.
    4. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)

    Excluded medical conditions
    5. Any of the following as the only site(s) of disease: palpable lymph nodes not visible on imaging studies, skin lesions, or bone marrow involvement only.
    6. Active CTCAE Grade 3/4 infection
    7. Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; patients positive for anti-HCV will be eligible if they are negative for HCV-RNA
    8. Known history of human immunodeficiency virus (HIV) infection
    9. Current central nervous system (CNS) involvement by lymphoma
    - Any past history or evidence of current leptomeningeal involvement by lymphoma is prohibited.
    - Patients with prior localized CNS involvement who have been without recurrence for >= 12 mths and currently have a negative head MRI and negative cerebrospinal fluid (CSF) may be eligible.
    10. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 mths). Myocardial infarction within the past 6 months before start of study treatment
    11. Uncontrolled arterial hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management).
    12. Type I or II diabetes mellitus with HbA1c > 8.5% or
    fasting plasma glucose > 160 mg/dL at Screening.
    13. New York Heart Association (NYHA) class III or IV heart disease.
    14. Any other malignancy within last 3 yrs except for the following, which are permitted:
    a. curatively treated non-melanoma skin cancer
    b. carcinoma in situ of the cervix
    c. in situ ductal carcinoma of the breast after complete resection
    d. superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
    15. Any illness or conditions (substance abuse, medical, psychological or social) that may interfere with the patient's participation in the study, evaluation of the study results, or could jeopardize the safety of the patient and his/her compliance in the study.
    16. Non-healing wound ulcer or bone fracture.
    17. Major surgical procedure or significant traumatic injury (as judged by the investigator) less than 28 days before start of study treatment.
    18. Patients with seizure disorder requiring medication.
    19. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event with CTCAE Grade >= 3 within 4 weeks prior to screening.
    20. Proteinuria of CTCAE Grade 3 or higher (> 3.5 measured by urine protein to creatinine ratio on a random urine sample)
    21. History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).
    22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of study treatment and a negative result must be documented before start of study treatment.
    23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia and <= CTCAE Grade 2 peripheral neuropathy. Patients with B symptoms are eligible for enrollment.

    Excluded previous therapies and medications:
    24. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of study treatment
    25. Radioimmunotherapy or autologous transplant less than 3 mths before start of study treatment
    26. Myeloid growth factors less than 7 days before start of study treatment
    27. Blood or platelet transfusion less than 7 days before start of study treatment
    28. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed dose (<= 15 mg of prednisone or equivalent) at least 7 days before performing the screening CT/MRI or PET-CT whichever is performed first and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the Screening. Patients may be using topical or inhaled corticosteroids.
    1. Asignación previa al tratamiento (TTO) durante este ensayo clínico (EC).Pacientes retirados definitivamente de la participación en el EC no volverán a entrar.2.Participación simultánea en otros EC.Deben completar su participación en otro ECcon un medicamento en investigación 28días antes del inicio del TTO o 5vidas medias del tratamiento en investigación, lo que sea mayor.3. TTO previo con copanlisib u otros inhibidores de la PI3K.4.Estrecha relación con el centro de investigación; p.ej.pariente cercano del investigador, persona dependiente (p.ej.empleado o estudiante del centro de investigación)
    Patologías clínicas excluidas:5.localización/es únicas de la enfermedad:ganglios linfáticos palpables no visibles en estudios de imagen,lesiones cutáneas o exclusivamente afectación de la médula ósea.6.Infección activa de grado 3/4 según CTCAE.7.Hepatitis B(HBV) o hepatitis C(HCV). Todos los pacientes deben realizarse las pruebas de HBV y HCV hasta 28días antes de empezar el TTO del estudio mediante el panel de rutina para la hepatitis disponible en el centro.Los pacientes positivos para HBsAg o HBcAb serán candidatos si son negativos para HBV-DNA;Los pacientes positivos a anti-HCV serán candidatos si son negativos a HCV-RNA.8.Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana(VIH).9.Afectación actual del sistema nervioso central(SNC) por linfoma:Se prohíbe cualquier historia pasada o evidencia de afectación leptomeníngea actual por el linfoma;Pueden ser elegibles los pacientes con afectación del SNC localizada previa sin recurrencia de >=12 meses y actualmente tienen una MRI craneal negativa y el líquido cefalorraquídeo negativo.10. Angina inestable(síntomas de angina en reposo),angina de nueva aparición(empezado en los últimos 3meses).Infarto de miocardio en los 6meses anteriores al inicio del tratamiento del estudio.11.HTA no controlada(presión arterial sistólica>150 mmHg o presión arterial diastólica>90 mmHg a pesar de tratamiento).12.Diabetes mellitus de tipo I o II con HbA1c>8,5 % o glucemia plasmática en ayunas>160 mg/dl en la selección.13.Cardiopatía de clase III o IV según la New York Heart Association.14.Cualquier tipo de cáncer 3 años antes de la inclusión en el EC, excepto:Cáncer de piel no melanoma tratados con intención curativa.Carcinoma in situ del cuello uterino.Carcinoma ductal in situ de la mama después de la resección completa.Tumores vesicales superficiales (estadificación:Ta,Tis y T1).15.Enfermedad o condiciones(Consumo de sustancias psicoactivas y trastornos médicos, psicológicos o sociales)que puedan interferir en la participación del paciente en el EC o en la evaluación de los resultados del EC.16.Úlcera sin cicatrizar o fractura ósea no consolidada.17.Intervención de cirugía mayor o lesión traumática significativa(a criterio del investigador)en 28días anteriores al inicio de la selección.18.Los pacientes con evidencia o historia de diátesis hemorrágica.Cualquier hemorragia o evento de sangrado de grado>=3 CTCAE, 4semanas antes de la selección.19.Proteinuria >=3 CTCAE (> 3,5 medido según el cociente proteína/creatinina en una muestra de orina al azar).20.Historia o condición concurrente de enfermedad pulmonar intersticial de cualquier gravedad y/o función pulmonar severamente dañada(a criterio del investigador).22.Mujeres embarazadas o en período de lactancia. Las mujeres fértiles deben dar negativo en prueba de embarazo en suero realizada en los 7días previos al inicio del TTO del estudio y se deberá obtener un resultado negativo antes de la primera dosis del fármaco.23.Toxicidad sin resolver >de grado 1 CTCAE, atribuible a cualquier TTO/procedimiento previo, excluyendo alopecia y neuropatía periférica ? 2CTCAE.Los pacientes con síntomas B son elegibles para la selección
    TTO y fármacos previos excluidos:24.Radioterapia o inmuno-/quimioterapia en las 4semanas anteriores al inicio del TTO del estudio.25.Radioinmunoterapia o trasplante autólogo en los 3meses anteriores al inicio del TTO del estudio.26.Factores de crecimiento mieloides en los 7días anteriores al inicio del TTO del estudio.27.Transfusión de sangre o de plaquetas en los 7días anteriores al inicio del TTO tratamiento del estudio.28. TTO con corticosteroides sistémicos en curso en una dosis diaria mayor de 15mg de prednisona o equivalente. La terapia con corticosteroides anterior debe detenerse o reducirse hasta la dosis permitida (<= 15 mg de prednisona o equivalente) al menos 7días antes de realizar la prueba CT / MRI o PET-CT de la selección (lo que se realice primero),y de nuevo antes de la primera administración del fármaco del estudio.Si un paciente está en t TTO crónico con corticosteroides, los corticosteroides deben des-escalarse hasta la dosis máxima permitida antes de la selección. Los pacientes pueden utilizar corticosteroides tópicos o inhalados
    E.5 End points
    E.5.1Primary end point(s)
    The primary variable is the objective Response Rate (ORR), defined as the proportion of patients who have at least once a post baseline overall response of CR (complete response) or PR (partial response) during study conduct; according to the criteria defined in The Lugano Classification.
    El objetivo principal del estudio es Tasa de respuesta objetiva (ORR), definida como la proporción de pacientes que tienen al menos una CR (respuesta completa) o PR (respuesta parcial) post selección durante la realización del estudio; de acuerdo con los criterios definidos en la Clasificación Lugano.
    E.5.1.1Timepoint(s) of evaluation of this end point
    It will be assessed 24 weeks after the last patient fully evaluable for the primary endpoint started treatment.
    Serán evaluadas 24 semanas después del último paciente completamente evaluable en tratamiento para el objetivo primario del estudio
    E.5.2Secondary end point(s)
    Duration of response (DOR);
    Progression-free survival (PFS);
    Overall survival (OS);
    Disease control rate (DCR);
    Duration of stable disease (DOSD).
    Duración de la respuesta (DOR);
    Progresión libre de enfermedad (PFS);
    Supervivencia global (OS);
    Indice control de enfermedad (DCR),
    Duración de la enfermedad estable (DOSD).
    E.5.2.1Timepoint(s) of evaluation of this end point
    The final analyses of all secondary efficacy and safety variables and an
    additional exploratory analysis of the primary efficacy variable will be
    performed 2 years after the last patient's first treatment or the last
    patient dies, whichever occurs first.
    El análisis final de todas las variables secundarias de seguridad y eficacia y análisis exploratorios adicionales de la variable primaria de eficacia se realizarán 2 años después de la última dosis del primer paciente o de la muesrte del último paciente, lo que antes ocurra
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic 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 Yes
    E.6.13.1Other scope of the trial description
    Biomarker analysis
    Análisis de biomarcadores
    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. 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Korea, Republic of
    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 study as a whole will be reached as soon as the last survival contact of the last patient has occurred in all centers in all participating countries (EU and non-EU)
    El final del estudio en su conjunto se alcanzará cuando se produzca el último contacto de supervivencia del último paciente en todos los centros en todos los países participantes (UE y no UE)
    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 months3
    E.8.9.1In the Member State concerned days3
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days3
    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: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 36
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 66
    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)
    After the end of study treatment, further therapy is at the discretion of the investigator.
    Después del tratamiento del estudio, las terapias siguientes serán a criterio del investigador
    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 Decision2015-06-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-05-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-19
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