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    Summary
    EudraCT Number:2013-003893-29
    Sponsor's Protocol Code Number:BAY80-6946/17067
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-03-27
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-003893-29
    A.3Full title of the trial
    A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma (iNHL) - CHRONOS-3
    Estudio fase III, aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia y seguridad de copanlisib en combinación con rituximab en pacientes con linfoma no Hodgkin de células B indolente tras recidiva (iNHL)-CHRONOS 3
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study investigating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin's lymphoma.
    Estudio que investiga la eficacia y la seguridad de copanlisib en combinación con rituximab en pacientes con linfoma no Hodgkin de células B indolente tras recidiva
    A.3.2Name or abbreviated title of the trial where available
    Copanlisib and rituximab in relapsed iNHL
    Copanlisib y rituximab en iLNH tras recidiva
    A.4.1Sponsor's protocol code numberBAY80-6946/17067
    A.5.4Other Identifiers
    Name:Pi3K InhibitorNumber: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 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.5.3.4CountryGermany
    B.5.4Telephone number0034900102372
    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 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 CodeSUB 32033
    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.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 RoleComparator
    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 MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRituximab
    D.3.4Pharmaceutical form 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboLyophilisate for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    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 B-cell non-Hodgkin's lymphoma
    Pacientes con linfoma no Hodgkin de células B indolente tras recidiva
    E.1.1.1Medical condition in easily understood language
    Relapsed indolent B-cell non-Hodgkin's lymphoma
    linfoma no Hodgkin de células B indolente tras recidiva
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10029600
    E.1.2Term Non-Hodgkin's lymphoma recurrent
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is:
    - To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab and alkylating agents, and who either had a treatment-free interval of >= 12 months after completion of the last rituximab-containing treatment, or for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
    El Objetivo primario del estudio es:
    Evaluar si copanlisib en combinación con rituximab es superior al placebo en combinación con rituximab para prolongar la supervivencia libre de progresión (SLP) en pacientes con LNH indolente tras recidiva que han recibido una o más líneas de tratamiento, incluidos rituximab y agentes alquilantes, y que tuvieron un intervalo sin tratamiento >= 12meses desde la finalización del último tratamiento con rituximab, o en los que esté contraindicada la quimioterapia por motivos de edad, enfermedades concomitantes y/o toxicidad residual
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate:
    - The following characteristics of disease-related symptoms: «time to deterioration» and «time to improvement»
    - Other radiological and clinical indicators of treatment efficacy
    - Safety and tolerability of copanlisib

    The other objectives of this study are to evaluate:
    - Pharmacokinetics
    - Biomarkers
    - Quality of life
    Los objetivos secundarios de este estudio son evaluar:
    - Las características siguientes de los síntomas relacionados con la enfermedad: «tiempo hasta el empeoramiento» y «tiempo hasta la mejoría»
    - Otros indicadores radiológicos y clínicos de eficacia del tratamiento
    - Seguridad y tolerabilidad de copanlisib

    Los demás objetivos de este estudio son evaluar:
    - Farmacocinética
    - Biomarcadores
    - Calidad de vida
    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 must be obtained before any study specific procedure.

    2. Histologically confirmed diagnosis of CD20 positive iNHL, with histological subtype limited to:
    - Follicular lymphoma (FL) grade 1-2-3a
    - Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at the time of diagnosis and at study entry
    - Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
    - Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)

    3. Patients must have relapsed after at least 1 prior line of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Patients must be not refractory to rituximab at any prior line of therapy (response shorter than 6 months from the end of any prior rituximab- containing treatment) but can be refractory to any non-rituximab containing regimen. Previous exposure to PI3K is acceptable provided there is no resistance (see also exclusion criterion 40).

    4. Non-WM patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Lugano Classification.

    5. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level >= 2 x upper limit of normal (ULN).

    6. Male or female patients >= 18 years of age

    7. ECOG performance status <= 2 (ECOG: Eastern Cooperative Oncology Group)

    8. Life expectancy of at least 3 months

    9. Availability of fresh tissue and/or archival tumor tissue at Screening

    10. Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the informed consent form until at least 3 months after the last study 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.

    11. Adequate baseline laboratory values collected no more than 7 days before starting study treatment:
    - Total bilirubin <= 1.5 x ULN (< 3 x ULN for patients with Gilbert-Meulengracht syndrome or for patients with cholestasis due to compressive adenopathies of the hepatic hilum)
    - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 x ULN (<= 5 x ULN for patients with liver involvement by lymphoma)
    - Lipase <= 1.5 x ULN
    - Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula
    - International normalized ratio (INR) and partial thromboplastin time (PTT) <= 1.5 x ULN
    - Platelet count >= 75,000 /mm3
    - Hemoglobin (Hb) >= 8 g/dL
    - Absolute neutrophil count (ANC) >= 1,000/mm3

    12. Left ventricular ejection fraction (LVEF) >= 45%

    13. Patients must either:
    - have had a treatment-free interval of at least 12 months after completion of the last rituximab-containing treatment
    OR
    - be considered unfit to receive chemotherapy on reason of age, concomitant morbidities, and/or residual toxicity from previous treatments. Patients in whom chemotherapy is contraindicated are defined by one of the following features:
    o Age >= 80 years
    o Age < 80 years and at least 1 of the following conditions:
    - at least 3 grade 3 CIRS-G comorbidities (see Appendix 14.7)
    OR
    - at least 1 grade 4 CIRS-G comorbidity (if compatible to participation in the study - see exclusion criterion no. 26).
    1. Capacidad de entender y estar dispuestos a firmar el consentimiento informado por escrito. Deberá obtenerse el consentimiento informado firmado antes de los procedimientos específicos del estudio

    2. Diagnóstico histológico confirmado de LNH indolente CD20 positivo con subtipo histológico limitado a:
    - Linfoma folicular (LF) de grado G1-2-3a
    - Linfoma linfocítico pequeño (LLP) con un recuento absoluto de linfocitos < 5x109/l en el momento del diagnóstico y en el momento de la inclusión
    - Linfoma linfoplasmocitoide / macroglobulinemia de Waldenström (LLP/MW)
    - Linfoma de la zona marginal (LZM) (esplénico, ganglionar o extraganglionar)

    3. Los pacientes deben haber presentado recidiva después de un mínimo de 1línea de tratamiento anterior, que incluyera rituximab y agentes alquilantes. Un tratamiento previo se define por uno de los siguientes supuestos: un mínimo de 2 meses de tratamiento con un único agente; un mínimo de 2 ciclos consecutivos de poliquimioterapia; trasplante autólogo; radioinmunoterapia. Se aceptará la exposición previa a PI3K siempre que no haya habido resistencia (ver también criterio exclusión 40)

    4. Los pacientes sin MW deben tener al menos una lesión medible bidimensionalmente (que no debe haber sido irradiada previamente), de acuerdo con las recomendaciones para la Evaluación, Estadificación y Valoración de la Respuesta Iniciales del linfoma de Hodgkin y no Hodgkin: clasificación de Lugano

    5. Los pacientes con MW que no tengan al menos una lesión medible bidimensionalmente en la evaluación radiológica basal deben presentar enfermedad medible, definida por la presencia de la paraproteína inmunoglobulina M (IgM), con un nivel máximo de IgM >= 2 veces el límite superior de la normalidad

    6. Pacientes de ambos sexos >= 18 años.

    7. Estado funcional del ECOG (Eastern Cooperative Oncology Group) <= 2

    8. Esperanza de vida mínima de 3 meses

    9. Disponibilidad de tejido tumoral fresco y/o tejido tumoral de archivo en el momento de la selección

    10. Las mujeres potencialmente fértiles y los hombres deberán aceptar la adopción de medidas anticonceptivas apropiadas cuando sean sexualmente activos. Esta condición tendrá vigencia desde la firma del consentimiento informado hasta un mínimo de 3 meses tras la última administración de la medicación del estudio. El investigador o un colaborador designado deberá aconsejar al paciente sobre métodos anticonceptivos aceptables. En el estudio, los método anticonceptivos aceptables se definen como cualquier método (o combinación de métodos) recomendado desde el punto de vista médico, según las normas asistenciales

    11. Valores analíticos basales aceptables, según evaluación en los 7 días previos al inicio del tratamiento del estudio:
    - Bilirrubina total <= 1,5 veces el LSN (< 3 veces el LSN en pacientes con síndrome de Gilbert-Meulengracht o en pacientes con colestasis debido a adenopatías compresivas en el hilio hepático).
    - Alanina-aminotransferasa (ALT) y aspartato-aminotransferasa (AST) <= 2,5 veces el LSN (<= 5 veces el LSN en pacientes con afectación del hígado por el linfoma)
    - lipasa <= 1,5 veces el LSN
    - Filtración glomerular (FG) >= 30 ml/min/1,73 m2 según la fórmula del estudio de modificación de la dieta en la enfermedad renal, Modification of Diet in Renal Disease (MDRD)
    - Cociente internacional normalizado (INR) y tiempo de tromboplastina parcial (TTP) <= 1,5 veces el LSN.
    - Cifra de plaquetas >= 75 000 células/mm3
    - Hemoglobina (Hb) >= 8 g/dl
    - Recuento absoluto de neutrófilos (RAN) >= 1000/mm3

    12. Fracción de eyección ventricular izquierda >= 45 %

    13. Los pacientes deben
    - Tener un intervalo sin tratamiento >= 12 meses desde la finalización del último tratamiento con rituximab
    O
    - Ser considerados no apto para recibir quimioterapia por motivos de edad, enfermedades concomitantes y/o toxicidad residual por tratamientos previos. Los pacientes en los que está contraindicada la quimioterapia se definen por una de las siguientes características:
    o Edad >= 80 años
    o Edad < 80 años y al menos 1 de las siguientes afecciones:
    - Al menos 3 enfermedades concomitantes de grado 3 según la escala CIRS-G (ver apendice 14.7)
    O
    - Al menos 1 enfermedad concomitante de grado 4 según la escala CIRS-G (si se considera compatible con la participación en el estudio - ver criterio de exclusión nº 26)
    E.4Principal exclusion criteria
    1. Previous assignment to treatment during this study.
    2. Close affiliation with the site.
    3. Histologically confirmed diagnosis of FL grade 3b or transformed disease, or chronic lymphocytic leukemia
    4. Last rituximab infusion within 12 mths of the start of the next treatment.
    5. Previous/concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 yrs prior to treatment start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis and T1), and asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for >=1 yr prior to randomization
    6. Known lymphomatous involvement of the central nervous system
    7. Congestive heart failure > New York Heart Association class 2
    8. Unstable angina, new-onset angina. Myocardial infarction less than 6 mths before start of test drug
    9. Uncontrolled arterial hypertension
    10. Type I or II diabetes mellitus with HbA1c >8.5% or fasting plasma glucose >160mg/dL at Screening
    11. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 mths before start of study treatment
    12. Non-healing wound, ulcer, or bone fracture
    13. Active, clinically serious infections > CTCAE Grade 2
    14. Known history of human immunodeficiency virus infection
    15. 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 antibody will be eligible if they are negative for HCV-RNA
    16. Patients with seizure disorder requiring medication
    17. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event >= CTCAE Grade 3 within 4 wks prior to the start of study treatment
    19. Proteinuria of CTCAE Grade 3 or higher
    20. History/concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
    21. Concurrent diagnosis of pheochromocytoma
    22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a max. of 7 days before start of treatment, and a negative result must be documented before start of treatment
    23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters
    24. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
    25. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
    26. Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study
    28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatment
    29. Ongoing immunosuppressive therapy
    30. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of treatment, unless evidence of progression since last treatment
    31. Radioimmunotherapy or autologous transplant less than 3 mths before start of treatment, unless evidence of progression since last treatment
    32. Myeloid growth factors less than 7 days before start of treatment
    33. Blood or platelet transfusion less than 7 days before start of treatment
    34. Ongoing systemic corticosteroid therapy at daily dose higher than 15mg prednisone/equivalent. Previous corticosteroid therapy must be stopped/reduced to the allowed dose 7 days before performing the screening CT/MRI and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the max. allowed dose before the screening. Patients may be using topical or inhaled corticosteroids.
    35. History of having received an allogeneic bone marrow or organ transplant
    36. Major surgical procedure/significant traumatic injury less than 28 days before start of treatment, open biopsy less than 7 days before start of treatment
    37. Anti-arrhythmic therapy
    38. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up visit.
    39. Use of inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up visit.
    40. Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors defined as:
    - No response at any time during therapy, or
    - Progression after any response or after stable disease within 6 mths from the end of the therapy with a PI3K inhibitor
    Por limitación de espacio solo se traducen los CE más relevantes:
    3.Dx. confirmado histológicamente de LF de grado 3b o enfermedad transformada o leucemia linfocítica crónica
    4.Última infusión de rituximab en los 12 meses previos al inicio del siguiente tto
    5.Neoplasia maligna previa o concurrente distinta del LNH de crecimiento lento en cuanto a localización primaria o histología en los 5 años anteriores al inicio del tratamiento, salvo cáncer de cuello de útero in situ tratado de forma curativa, cáncer de piel no melanoma y tumores de vejiga superficiales (Ta, Tis y T1) y cancer de prostata asintomatico sin metastasis conocidas que no requiera tto o solamente tto hormonal y con antigeno especifico de prostata normal >=1 año antes de la randomización
    6.Afectación linfomatosa conocida del SNC
    7.Insuficiencia cardíaca congestiva de clase >II NYHA
    8.Angina inestable, angina de nueva aparición. Infarto de miocardio menos de 6 meses antes del inicio del fármaco del estudio
    9.HTA no controlada
    10.DM de tipo I o II con HbA1c > 8,5 % o glucemia en ayunas > 160 mg/dl en la selección
    11.Acontecimientos embólicos o trombóticos venosos o arteriales como accidente cerebrovascular, trombosis venosa profunda o embolia pulmonar en los 3 meses anteriores al inicio del tto de estudio
    14.Antecedentes conocidos de VIH
    15.Hepatitis B(VHB) o C(VHC). Se deberá volver a realizar pruebas de detección del VHB y C a todos los pacientes hasta 28 días antes del inicio del fármaco del estudio, utilizando las pruebas analíticas habituales para la detección de los v. de la hepatitis. Los pacientes con positividad para HBsAg o HBcAb serán elegibles si presentan negatividad para ADN-VHB; los pacientes con positividad para anticuerpos anti-VHC serán elegibles si presentan negatividad para ARN-VHC
    17.Pacientes con signos o antecedentes de diátesis hemorrágica Cualquier hemorragia o episodio hemorrágico de grado >= 3 según los CTCAE en las 4 semanas previas al inicio del tto de estudio
    19.Proteinuria >= grado 3 según los CTCAE
    20.Antecedentes o presencia de enfermedad pulmonar intersticial o deterioro grave de la función pulmonar
    21.Diagnóstico concurrente de feocromocitoma
    23.Toxicidad no resuelta de grado >1 según los CTCAE atribuida a cualquier tto o procedimiento previo, salvo alopecia, neuropatia periferica o parametros de medula osea
    24.Hipersensibilidad conocida a cualquiera de los fármacos del estudio, clases de los fármacos del estudio o excipientes de la formulación
    25.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
    26.Cualquier enfermedad o afección médica que sea inestable o que pueda poner en peligro la seguridad del paciente y su cumplimiento terapéutico en el estudio
    28.Tto con cualquier fármaco en investigación, aparte de inhibidores de la PI3K, en los últimos 28 días antes del inicio del tto a menos que haya evidencia de progresión desde el último tto
    29.Tto inmunosupresor en curso
    30.Radioterapia o inmuno/quimioterapia en las 4 semanas previas al inicio del tto, a menos que haya evidencia de progresión desde el último tto
    31.Radioinmunoterapia o trasplante autólogo en los 3 meses previos al inicio del tto, a menos que haya evidencia de progresión desde el último tto
    32.Factores de crecimiento mieloide durante los 14 días previos al inicio del tto
    33.Transfusión de sangre o de plaquetas durante los 14 días previos al inicio del tto
    34.Tto sistémico en curso con corticosteroides en una dosis diaria superior a 15 mg de prednisona o equivalente. El tto previo con corticosteroides debe haberse interrumpido o reducido a la dosis permitida 7 días antes de la realización de TC/RM de selección y, de nuevo, antes de la 1era administración del fármaco del estudio. Si el paciente está recibiendo tto crónico con corticosteroides, deberá reducirse su dosis de forma progresiva antes de la selección hasta la dosis máxima permitida. Los pacientes podrán estar usando corticosteroides tópicos o inhalados
    35.Antecedentes de trasplante alogénico de médula ósea o de algún órgano.
    36.Intervención quirúrgica mayor o lesión traumática grave en los 28 días previos al inicio del tto, biopsia abierta en los 7 días previos al inicio del tto
    37.Tto antiarrítmico
    38.Se prohíbe el uso de inhibidores potentes de CYP3A4 desde el día -14 del c1 hasta la visita de seguimiento de seguridad
    40.Evidencia de resistencia a tto previo con idelalisib o otros inhibidors PI3K definida como:
    - No respuesta en todo momento o
    - Progresion despues de cualquier respuesta o enf. estable en los 6 meses desde el fin del tto con inhibidor de PI3K
    E.5 End points
    E.5.1Primary end point(s)
    Progression free survival (PFS)
    Supervivencia libre de progresión (SLP)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time (in days) from randomization to PD or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will be censored at Day 1.
    El tiempo (en días) desde la aleatorización hasta que se produce PE o muerte por cualquier causa (si no se documenta progresión). Para este cálculo se usará la fecha real de las evaluaciones del tumor. La SLP en los pacientes sin PE o vivos en el momento del análisis se censurará en la fecha de su última evaluación del tumor. La SLP en los pacientes que no tengan evaluaciones tumorales ni hayan muerto después del período basal se censurará en el día 1.
    E.5.2Secondary end point(s)
    - Objective tumor response rate (ORR)
    - Duration of response (DOR)
    - Complete response rate (CRR)
    - Time to progression (TTP)
    - Overall survival (OS)
    - Time to deterioration in DRS-P
    - Time to improvement in DRS-P
    - Tasa de respuesta tumoral objetiva (TRO)
    - Duración de la respuesta (DR)
    - Tasa de respuesta completa (TRC)
    - Tiempo hasta la progresión (THP)
    - Supervivencia global (SG)
    - Tiempo hasta el empeoramiento de los SRE-F
    - Tiempo hasta la mejoria de los SRE-F
    E.5.2.1Timepoint(s) of evaluation of this end point
    - ORR - assessed in all patients up to the time of analysis of PFS.
    - DOR: time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until PD or death from any cause, whichever is earlier
    - CRR: assessed in all patients up to the time of analysis of PFS.
    - TTP: time from randomization to PD or death related to PD, whichever is earlier
    - OS: time (in days) from randomization until death from any cause.
    - Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire.
    - Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less.
    - TRO- evaluada en todos los pacientes hasta el momento del análisis de la SLP
    - DR: tiempo (en días) desde la primera observación de respuest tumoral (RC o RP) hasta PE o muerte por cualquier causa, lo que suceda primero
    - TRC: evaluada en todos los pacientes hasta el momento del análisis de la SLP
    - THP: tiempo transcurrido desde la aleatorización hasta la PE o muerte relacionada con la PE, lo que suceda primero
    - SG: tiempo (en días) desde la aleatorización hasta la muerte por cualquier causa
    - Tiempo hasta el empeoramiento de los SRE-F en almenos 3 puntos del cuestionario FLymSI-18
    - Tiempor hasta la mejoria de los SRE-F en almenos 3 puntos, medidos en el cuestionario FLymSI-18, será evaluado en los pacientes con un SRE-F de 30 puntos o menos.
    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
    Biomarkers and Quality of Life
    Biomarcadores y Calidad de vida
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) Yes
    E.8.2.2Placebo Yes
    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 EEA60
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Bulgaria
    Chile
    China
    Colombia
    Czech Republic
    Denmark
    France
    Germany
    Hong Kong
    Hungary
    Ireland
    Italy
    Korea, Democratic People's Republic of
    Lithuania
    Mexico
    Philippines
    Poland
    Portugal
    Russian Federation
    Singapore
    South Africa
    Spain
    Sweden
    Taiwan
    Thailand
    Turkey
    Ukraine
    United States
    Vietnam
    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
    For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the LVLS for all centers in the respective country has occurred.

    The end of study as a whole will be reached as soon as the end of the study according to the above definition has been reached in all participating countries (EU and non-EU).

    The end of study notification to Health Authorities will be based on the completion of the collection of survival data.
    Para todos los países de la UE, y de acuerdo con la Directiva EU de EECC, el final del estudio tendrá lugar cuando se haya realizado última visita último paciente en todos los centros del país.
    La finalización del estudio en su conjunto se producirá cuando el final del estudio (parrafo anterior) se haya conseguido en todos los países (UE y no UE).
    La notificación de la finalización del estudio a las autoridades sanitarias 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 years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days30
    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: 227
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 340
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 567
    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 this study, further therapy is at the discretion of the investigator.
    Después de la finalización del estudio, cualquier otro tratamiento que reciba el paciente queda 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 Decision2015-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-27
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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