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    Summary
    EudraCT Number:2012-002602-52
    Sponsor's Protocol Code Number:BAY80-6946/16349
    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:2012-10-02
    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 number2012-002602-52
    A.3Full title of the trial
    Open-label, uncontrolled Phase II trial of intravenous PI3K inhibitor BAY 80-6946 in patients with relapsed, indolent or aggressive Non-Hodgkin's lymphomas
    Ensayo fase II, abierto, no controlado del inhibidor PI3K intravenoso BAY80-6946 en pacientes con linfoma No Hodgkin indolente o agresivo tras recaída
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase II PI3K inhibitor in relapsed, indolent or aggressive NHL
    Ensayo Fase II del inhibidor PI3K en linfoma No Hodgkin indolente o agresivo tras recaída.
    A.3.2Name or abbreviated title of the trial where available
    Phase II PI3K inhibitor in relapsed, indolent or aggressive NHL
    Ensayo Fase II del inhibidor PI3K en linfoma No Hodgkin indolente o agresivo tras recaída.
    A.4.1Sponsor's protocol code numberBAY80-6946/16349
    A.5.4Other Identifiers
    Name:Pi3KNumber:BAY80-6946
    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.1.3.4CountryGermany
    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.4.2CountryGermany
    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 Clinical Trials Contact
    B.5.3 Address:
    B.5.3.1Street AddressCTP Team/Ref:"EU CTR"/S102 - R156
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13343
    B.5.3.4CountryGermany
    B.5.6E-mailclinical-trials-contact@bayerhealthcare.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBAY84-1236 phosphatidylinositol-3 kinase (PI3K) inhibitor
    D.3.2Product code BAY84-1236
    D.3.4Pharmaceutical form Powder 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 (for BAY 80-6946)
    D.3.9.1CAS number not yet av.
    D.3.9.2Current sponsor codeBAY 84-1236
    D.3.9.3Other descriptive nameBAY 80-6946 (free base)
    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 number23.04
    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 relapsed, indolent or aggressive Non Hodgkin's lymphomas
    Pacientes diagnosticados de linfoma Non Hodgkin's indolente o agresivo tras recaída.
    E.1.1.1Medical condition in easily understood language
    Patients with relapsed, indolent or aggressive Non Hodgkin's lymphomas
    Pacientes diagnosticados de linfoma Non Hodgkin's indolente o agresivo tras recaída.
    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 objective of this study is to evaluate the efficacy and safety of BAY 80 6946 in patients with indolent or aggressive Non-Hodgkin's Lymphoma (NHL) who have progressed after standard therapy.
    El objetivo de este estudio es evaluar la eficacia y la seguridad de BAY 80-6946 en pacientes con LNH indolente o agresivo que han progresado después de recibir la terapia estandard.
    E.2.2Secondary objectives of the trial
    Further objectives are to evaluate the pharmacokinetics of BAY 80-6946 and biomarkers.
    Otros objetivos son evaluar la farmacocinética de BAY 80-6946 y biomarcadores.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    All inclusion criteria must be met at the time of screening.
    Indolent NHL:
    ? Histologically confirmed diagnosis of follicular lymphoma (FL), marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL).
    ? Relapsed after >= 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy- and/or immunotherapy-based regimens.
    Aggressive NHL:
    ? Histologically confirmed diagnosis of Grade 3 follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma, or anaplastic large cell lymphoma.
    ? Relapsed after >= 2 prior chemotherapy regimens, including the following: first-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination chemotherapy regimen. Patients refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL or not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic cells must have received prior rituximab, if available.
    Applicable to all patients:
    ? Ability to understand and willingness to sign written informed consent (IC). Signed informed consent must be obtained before any study specific procedure.
    ? Male or female patients > 18 years of age.
    ? Patients with NHL must have at least one measurable lesion according to the recommen-dations of the Report of an International Workshop to Standardize Response Criteria for NHL.
    ? ECOG performance status <= 2.
    ? Life expectancy of at least 3 months.
    ? Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last test drug administration. 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 recommended method (or combination of methods) as per standard of care. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for patients or their partners is required unless the woman has had a hysterectomy.
    ? Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment:
    - Total bilirubin <= 1.5 x the upper limit of normal (ULN) (< 3 x ULN for patients with Gilbert-Meulengracht syndrome).
    - Alanine transaminase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN (< 5 x ULN for patients with lymphomatous liver involvement of their cancer).
    - Amylase and lipase <= 1.5 x the ULN
    - Serum creatinine <= 1.5 x the ULN.
    - Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m2 according to the modified diet in renal disease (MDRD) abbreviated formula.
    - International normalized ratio (INR) or 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 of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
    - Platelet count >= 75,000 /mm3, hemoglobin (Hb) >= 9 g/dL, absolute neutrophil count (ANC) >= 1,500/mm3
    - Alkaline phosphatase limit <= 2.5 x ULN (<= 5 x ULN for patients with liver involvement of their cancer).
    ? Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN) for the Institution
    En el momento de la selección deberán cumplirse todos los criterios de inclusión.
    LNH indolente:
    ? Diagnóstico histológico confirmado de linfoma folicular (LF), linfoma de la zona marginal (incluido el linfoma de célula B de zona marginal nodal o esplénico y el linfoma del tejido linfoide asociado a mucosas [MALT]), linfoma linfoplasmacítico/macroglobulinemia de Waldenström, leucemia linfocítica crónica (LLC)
    ? Recaída tras >= 2 líneas previas de quimioterapia o inmunoterapia para el LNH indolente, o resistente a 2 líneas previas de quimioterapia y/o inmunoterapia.

    LNH agresivo:
    ? Diagnóstico histológico confirmado de linfoma folicular (LF) de grado 3, linfoma indolente transformado, linfoma B difuso de célula grande (LBDCG) , linfoma mediastínico de células B grandes, linfoma de células del manto (LCM), linfoma periféricos de células T, o linfoma anaplásico de células grandes.
    ? Recaída tras >= 2 líneas de quimioterapia anteriores, incluidas las siguientes: tratamiento de primera línea con una línea habitual con antraciclinas (p. ej., ciclofosfamida, doxorubicina, vincristina y prednisona o equivalente). Al menos 1 línea de quimioterapia combinada adicional. Pacientes resistentes a la primera línea previa de quimioterapia y/o inmunoterapia para un LNH agresivo o no candidatos a una línea de dosis altas seguidas por trasplante. La quimioterapia de dosis altas o la quimiorradioterapia con trasplante autólogo de células madre se considera 1 línea. Los pacientes con células neoplásicas que expresan CD20 tienen que haber recibido con anterioridad rituximab, si está disponible.
    Aplicable a todos los pacientes:
    ? Los pacientes deberán ser capaces de comprender un consentimiento informado (CI) por escrito y estar dispuestos a firmarlo. Deberá obtenerse el consentimiento informado firmado antes de los procedimientos específicos del estudio.
    ? Pacientes varones o mujeres > 18 años de edad.
    ? Los pacientes con LNH deben tener al menos una lesión medible de acuerdo con las recomendaciones del Report of an International Workshop to Standardize Response Criteria for NHL [22].
    ? Estado funcional del ECOG <= 2.
    ? Esperanza de vida mínima de 3 meses.
    ? Las mujeres en edad fértil y los varones deberán aceptar el uso de métodos anticonceptivos desde la firma del formulario de consentimiento informado hasta al menos 3 meses después de la administración de la última dosis del fármaco del estudio. El investigador o un colaborador designado deberá aconsejar al paciente cómo hacer un control de la natalidad adecuado. La anticoncepción adecuada se define en este estudio como el uso de cualquier método (o combinación de métodos) recomendado médicamente según el tratamiento habitual. La anticoncepción adecuada incluye la anticoncepción hormonal con implantes o anticonceptivos orales, transdérmicos o inyectables, ciertos dispositivos intrauterinos, ligadura bilateral de trompas, histerectomía o vasectomía de la pareja. Además, es necesario que los pacientes o sus parejas utilicen preservativos, a menos que la mujer se haya sometido a una histerectomía.
    ? Función medular, hepática y renal adecuadas, según evaluación de los siguientes parámetros de laboratorio, que se medirán en los 7 días previos al inicio del tratamiento del estudio:
    o Bilirrubina total <= 1,5 veces el límite superior de la normalidad (LSN) (<3 veces el LSN en pacientes con síndrome de Gilbert-Meulengracht).
    o Alanina transaminasa (ALT) y aspartato-aminotransferasa (AST) <= 2,5 veces el LSN (< 5 veces el LSN para pacientes con afectación linfomatosa del hígado por su cáncer)
    o Amilasa y lipasa <= 1,5 veces el LSN
    o Creatinina sérica <= 1,5 veces el LSN
    o Tasa de filtración glomerular (TFG) >= 30 ml/min/1,73 m2 según la fórmula abreviada de la dieta modificada en la enfermedad renal (MDRD)
    o Cociente internacional normalizado (INR) o tiempo de tromboplastina parcial (TTP) < 1,5 veces el LSN. Los pacientes que estén recibiendo tratamiento con un fármaco como warfarina o heparina podrán participar siempre que no existan indicios previos de anomalías subyacentes de los parámetros de coagulación. Se realizará un estrecho control con, al menos, análisis semanales hasta que el INR/TTP sea estable según un resultado obtenido antes de la administración, conforme se defina en el procedimiento local.
    o Número de plaquetas >= 75.000/mm3, hemoglobina (Hb) >= 9 g/dl, recuento absoluto de neutrófilos (RAN) >= 1.500/mm3
    o Límite de fosfatasa alcalina <= 2,5 veces el LSN (<= 5 veces el LSN para pacientes con afectación hepática por su cáncer)
    ? Fracción de eyección ventricular izquierda (FEVI) >= límite inferior de la normalidad (LIN) utilizado en el centro
    E.4Principal exclusion criteria
    Patients who meet any of the following criteria at the time of screening will be excluded:
    Excluded medical conditions:
    ? Previous or concurrent cancer that is distinct in primary site or histology from cancer of the lymphatic system within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
    ? Symptomatic lymphomatous involvement of the brain.
    ? Congestive heart failure > New York Heart Association (NYHA) class 2.
    ? Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of test drug.
    ? Uncontrolled hypertension. (Blood pressure >= 150/90 mmHg despite optimal medical management).
    ? Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication.
    ? Non-healing wound, ulcer, or bone fracture.
    ? Active clinically serious infections (> CTCAE grade 2).
    ? Known history of human immunodeficiency virus (HIV) infection.
    ? Known history of chronic hepatitis B or C.
    ? Patients with seizure disorder requiring medication.
    ? Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >= CTCAE Grade 3 within 4 weeks of start of study medication.
    ? Renal failure requiring hemo-or peritoneal dialysis.
    ? Dehydration of CTCAE grade >= 1 (NCI-CTC version 4.0).
    ? Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
    ? Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation.
    ? History or concurrent condition of interstitial lung disease.
    ? Persistent proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: creatinine ratio on a random urine sample).
    ? Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia.
    ? Current diagnosis of Type 1 or 2 diabetes mellitus, fasting blood glucose > 125 mg/dL (> 6.9 mmol/L) or HbA1c >= 7.0 %
    ? Patients with phaeochromocytoma.
    ? Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
    ? 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).
    ? Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study (see also Section 6.9 and Appendix 14.2).
    ? Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.

    Excluded previous therapies and medications:
    ? Prior treatment with PI3K inhibitors.
    ? Treatment with investigational drugs other than PI3K inhibitors within the last 28 days.
    ? Ongoing immunosuppressive therapy.
    ? Radiotherapy within 4 weeks prior to treatment start.
    ? Systemic corticosteroid therapy (ongoing). Patients may be using topical or inhaled corticosteroids.
    ? History of having received an allogeneic bone marrow or organ transplant
    ? Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication.
    ? Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
    ? Use of strong inhibitors of CYP3A4 is prohibited from Day -14 and for the duration of the study
    ? Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 and for the duration of the study.
    Los pacientes que cumplan cualquiera de los siguientes criterios en el momento de la selección serán excluidos:
    Enfermedades médicas excluidas:
    ? Cáncer anterior o concurrente distinto del cáncer del sistema linfático en lo que concierne al lugar primario o a la histología en los 5 años anteriores a la selección SALVO el cáncer de cuello de útero in situ tratado de forma curativa, el cáncer de piel no melanoma y los tumores de vejiga superficiales [Ta (tumor no agresivo), Tis (carcinoma in situ) y T1 (tumor que invade la lamina propia)].
    ? Afectación linfomatosa sintomática cerebral.
    ? Insuficiencia cardíaca congestiva de clase > 2 de la New York Heart Association (NHYA)
    ? Angina inestable (síntomas de angina en reposo), angina de nueva aparición (que ha empezado en los últimos 3 meses). Infarto de miocardio de menos de 6 meses antes del inicio del fármaco del estudio.
    ? Hipertensión no controlada (presión arterial >= 150/90 mm Hg a pesar del tratamiento médico óptimo).
    ? Episodios embólicos o trombóticos venosos o arteriales, como un accidente cerebrovascular (incluidos accidentes isquémicos transitorios), trombosis venosa profunda o embolia pulmonar en los 6 meses anteriores al inicio del medicamento del estudio.
    ? Herida, úlcera o fractura ósea no cicatrizadas.
    ? Infecciones graves clínicamente activas (de grado >2 de los CTCAE).
    ? Infección por el virus de la inmunodeficiencia humana (VIH) diagnosticada.
    ? hepatitis B o C crónica diagnosticada.
    ? Pacientes con trastornos convulsivos que requieran medicación.
    ? Pacientes con indicios o antecedentes de diátesis hemorrágica. Cualquier hemorragia o episodio hemorrágico de grado >= 3 de los CTCAE en las 4 semanas previas al inicio del tratamiento del estudio.
    ? Insuficiencia renal que requiere hemodiálisis o diálisis peritoneal.
    ? Deshidratación de grado >= 1 de los CTCAE (NCI-CTC versión 4.0).
    ? Consumo de sustancias psicoactivas y trastornos médicos, psicológicos o sociales que puedan interferir en la participación del paciente en el estudio o en la evaluación de los resultados del estudio.
    ? Hipersensibilidad conocida a cualquier fármaco del tratamiento del estudio, clases de los fármacos del estudio o excipientes de la formulación.
    ? Antecedentes de neumopatía intersticial o neumopatía intersticial concurrente.
    ? Proteinuria persistente de grado 3 de los CTCAE o mayor (> 3,5 g/24 h, medida por las proteínas en orina: indice de creatinina en una muestra aleatoria de orina).
    ? Toxicidad no resuelta de grado mayor a 1 de los CTCAE (NCI-CTC versión 4.0) atribuida a cualquier tratamiento o procedimiento previo, excepto alopecia.
    ? Diagnóstico actual de diabetes mellitus de tipo 1 o 2, glucemia en ayunas > 125 mg/dl (>6,9 mmol/l) o HgbA1c >= 7%.
    ? Pacientes con feocromocitoma.
    ? Embarazo o lactancia. Las mujeres en edad fértil deberán someterse a una prueba de embarazo un máximo de 7 días antes del inicio del tratamiento del estudio y se deberá documentar un resultado negativo antes del inicio del tratamiento del estudio.
    ? Estrecha afiliación con el centro de investigación; p. ej., un familiar próximo del investigador, persona dependiente (p. ej., empleado o estudiante del centro de investigación).
    ? Cualquier enfermedad o afección médica que sea inestable o que pueda poner en peligro la seguridad del paciente y de su cumplimiento terapéutico en el estudio (véase también el Apartado 6.9 y el Anexo 14.2).
    ? Asignación previa a un tratamiento durante este estudio. Los pacientes retirados permanentemente de la participación en el estudio no podrán ser readmitidos.

    Tratamientos y medicamentos previos excluidos:
    ? Tratamiento previo con inhibidores de la PI3K.
    ? Tratamiento con cualquier fármaco experimental aparte de inhibidores de la PI3K en los últimos 28 días.
    ? Tratamiento inmunosupresor en curso.
    ? Radioterapia en las 4 semanas previas al inicio del tratamiento.
    ? Corticoterapia sistémica (en curso). Los pacientes pueden estar usando corticoesteroides tópicos o inhalados.
    ? Antecedentes de trasplante alogénico de médula ósea o de órgano.
    ? Actuación quirúrgica mayor, biopsia abierta o lesión traumática grave en los 28 días previos al inicio de la medicación del estudio.
    ? Arritmias cardíacas que requieran tratamiento antiarrítmico (los betabloqueantes o la digoxina están permitidos).
    ? Se prohíbe el uso de inhibidores potentes de la CYP3A4 desde el día -14 y durante todo el estudio
    ? Se prohíbe el uso de inductores potentes de la CYP3A4 desde el día -14 del ciclo 1 y durante todo el estudio
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable will be the objective tumor response (OR).
    OR will be assessed in all patients up to 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment.
    La variable principal de eficacia será la respuesta objetiva del tumor (RO). La RO se evaluará en todos los pacientes hasta 16 semanas después que el último paciente completamente evaluable respecto a la variable principal haya comenzado el tratamiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of the primary efficacy variable will be performed 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment. At that timepoint, an exploratory analysis of all other variables will be performed, if possible.
    La variable principal de eficacia se evaluará en todos los pacientes a las 16 semanas después que el último paciente completamente evaluable respecto a la variable principal haya comenzado el tratamiento. En ese momento, se realizará un análisis exploratorios del resto de variables, si es posible
    E.5.2Secondary end point(s)
    Secondary efficacy variables in this study will be:
    ? Duration of response (DOR), defined as the time (in days) from first observed tumor response (CR, CRu [applicable only in patients with NHL] or PR) until PD or until death caused by PD.
    ? Progression free survival (PFS), defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression).
    ? Overall survival (OS), defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive.
    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 3 years after the last patient's first treatment or when all patients got PD, whatever comes first.
    El análisis final de todas las variables secundarias de eficacia y seguridad y el análisis exploratorio adicional de la variable principal de eficacia se llevarán a cabo 3 años después del primer tratamiento del último paciente o cuando todos los pacientes alcancen la progresión de la enfermedad (PD), lo que primero suceda
    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
    tumor response
    Respuesta tumoral
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    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 trial2
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA35
    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
    Finland
    France
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    Thirty to 35 days after discontinuation of study treatment, a safety follow-up visit will be performed for the collection of adverse events (AEs) and concomitant medication data. Patients will be contacted quarterly to determine overall survival status up to 3 years after last patient first treatment.
    The end of study notification to Health Authorities will be based on the completion of the collection of survival data.
    Entre 30 y 35 días después de la suspensión del tratamiento del estudio se realizará una visita de seguimiento de la seguridad para la recogida de acontecimientos adversos y de datos de los medicamentos concomitantes. Se contactará cada trimestre con los pacientes para determinar el estado de supervivencia global hasta 3 años después del 1er tratamiento del último paciente.La notificación del final del estudio a las autoridades se realizará al finalizar la recogida de datos de supervivencia.
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 60
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-10
    P. End of Trial
    P.End of Trial StatusOngoing
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