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    EudraCT Number:2019-001573-89
    Sponsor's Protocol Code Number:D8220C00008
    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:2019-07-04
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-001573-89
    A.3Full title of the trial
    A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects with Chronic Lymphocytic Leukemia
    Estudio de fase 3b, multicéntrico, abierto y con un solo grupo, de acalabrutinib (ACP-196) en sujetos con leucemia linfocítica crónica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment with Acalabrutinib in patients with chronic lymphocytic leukemia
    Tratamiento con acalabrutinib en pacientes con leucemia linfocítica crónica
    A.4.1Sponsor's protocol code numberD8220C00008
    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 SponsorAstraZeneca AB
    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 supportAstraZeneca AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post code19850-5437
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018002369933
    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 nameAcalabrutinib
    D.3.2Product code ACP-196
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAcalabrutinib
    D.3.9.1CAS number 1420477-60-6
    D.3.9.2Current sponsor codeACP-196
    D.3.9.3Other descriptive nameACP-196
    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 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
    Chronic lymphocytic leukemia
    Leucemia linfocítica crónica
    E.1.1.1Medical condition in easily understood language
    Patients with chronic lymphocytic leukemia in need of treatment
    Pacientes con leucemia linfocítica crónica con necesidad de tratamiento
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of acalabrutinib monotherapy in subjects with treatment-naive or relapsed/refractory chronic lymphocytic leukemia
    Evaluar la seguridad y la tolerabilidad del acalabrutinib en monoterapia en sujetos con leucemia linfocítica crónica no tratados previamente o en recidiva/refractarios
    E.2.2Secondary objectives of the trial
    To evaluate the investigator-assessed overall response rate, duration of response, and progression-free survival in subjects receiving acalabrutinib monotherapy;
    Evaluar la tasa de respuesta global, la duración de la respuesta y la supervivencia sin progresión, según la valoración del investigador, en sujetos tratados con acalabrutinib en monoterapia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Men and women >=18 years of age;
    2. Diagnosis of CLL that meets published diagnostic criteria:
    a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing >=1 B-cell marker (CD19, CD20, and CD23) and CD5;
    b. Prolymphocytes may comprise <55% of blood lymphocytes;
    c. Presence of>=5 × 10^9 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis);
    3. Active disease per IWCLL 2018 criteria that requires treatment:
    a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/μL).
    b. Massive (i.e., >=6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
    c. Massive nodes (i.e., >=10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
    d. Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of <30x109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
    e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
    f. B-symptoms documented in the participants chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs (please refer to protocol for related symptoms);
    4. Must meet 1 of the following criteria:
    a. Have received no prior therapy for treatment of CLL and meets 1 of the following criteria:
    i. A score of >6 on the Cumulative Illness Rating Scale (CIRS).
    ii. Creatinine clearance of 30 to 69 ml/min using the Cockcroft-Gault equation.
    b. Have previously received therapy for CLL and have either refractory or relapsed CLL.
    c. Have received prior BTKi therapy (i.e., defined as a participant who discontinued a BTKi for any reason except disease progression) for CLL.
    d. Have either TN or R/R CLL and are receiving concomitant vitamin K antagonists (e.g., coumadin).
    5. ECOG performance status of <=2;
    6. Female subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use >= highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide during the study.
    7. Fluorescence in situ hybridization (FISH) results within 60 days before screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Participants must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
    8. Participants must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
    1. Hombres y mujeres >=18 años
    2. Diagnóstico de leucemia linfocítica crónica (chronic lymphocytic leukemia, CLL) de acuerdo con los siguientes criterios publicados (Halleket et al. 2018):
    a. Linfocitos B monoclonales (con restricción de las cadenas ligeras kappa o lambda) con coexpresión clonal de >=1 marcador de los linfocitos B (CD19, CD20 y CD23) y CD5
    b. Prolinfocitos <55% de los linfocitos en sangre
    c. Presencia de linfocitos B >=5 × 109/l (5000/μl) en sangre periférica (en cualquier momento desde el diagnóstico inicial)
    3. Enfermedad activa según los criterios IWCLL 2018 que requiera tratamiento
    a. Signos de insuficiencia medular progresiva, manifestada por aparición o empeoramiento de anemia (hemoglobina <10 g/dl) y/o trombocitopenia (plaquetas <100 000/μl)
    b. Esplenomegalia masiva (es decir, >=6 cm por debajo del reborde costal izquierdo), progresiva o sintomática
    c. Adenopatías masivas (es decir, >=10 cm de diámetro mayor), progresivas o sintomáticas
    d. Linfocitosis progresiva con aumento >50% durante un periodo de 2 meses o tiempo de duplicación de los linfocitos (lymphocyte doubling time, LDT) <6 meses. El LDT podrá obtenerse mediante extrapolación de regresión lineal de las cifras absolutas de linfocitos obtenidas a intervalos de 2 semanas durante un periodo de observación de 2 a 3 meses. En los sujetos con una cifra inicial de linfocitos en sangre <30 × 109/l (30 000/μl), no podrá emplearse el LDT como único parámetro para definir la indicación de tratamiento. Además, han de descartarse factores que pudieran contribuir a la presencia de linfocitosis o adenopatías aparte de la CLL (por ejemplo, infecciones).
    e. Anemia y/o trombocitopenia autoinmunitarias con escasa respuesta al tratamiento habitual
    f. Síntomas B documentados en la historia clínica del sujeto con medidas objetivas de apoyo, según proceda, definidos como >=1 de los siguientes síntomas o signos relacionados con la enfermedad:
    o Pérdida de peso involuntaria >=10% en los 6 meses previos a la selección
    o Cansancio acusado (estado funcional del Eastern Cooperative Oncology Group [ECOG] >=2; incapacidad para trabajar o realizar las actividades habituales)
    o Fiebre superior a 38,0 °C (100,5 °F) durante >=2 semanas antes de la selección sin signos de infección
    o Sudoración nocturna durante >=1 mes antes de la selección sin signos de infección
    4. Cumplimento de 1 de los siguientes criterios:
    a. No recepción de tratamiento previo para la CLL y cumplimiento de 1 de los siguientes criterios:
    i. Puntuación de la Cumulative Illness Rating Scale (CIRS) >6 (Appendix G)
    ii. Aclaramiento de creatinina de 30 a 69 ml/min según la ecuación de Cockcroft-Gault
    b. Recepción de tratamiento previo para la CLL y presencia de CLL refractaria o recidivante
    c. Recepción de tratamiento previo con un inhibidor de la tirosina-cinasa de Bruton (Bruton tyrosine kinase inhibitor, BTKi) (es decir, sujeto que haya suspendido un BTKi por cualquier motivo, excepto progresión de la enfermedad) para la CLL
    d. Presencia de CLL sin tratamiento previo (treatment-naive, TN) o en recidiva/refractaria (relapsed/refractory, R/R) y recepción concomitante de antagonistas de la vitamina K (por ejemplo, warfarina o acenocumarol)
    5. Estado funcional del ECOG <=2
    6. Las mujeres potencialmente fértiles (es decir, no esterilizadas quirúrgicamente ni posmenopáusicas) que mantengan relaciones sexuales con varones no esterilizados deberán utilizar >=1 método anticonceptivo altamente efectivo desde el momento de la selección y estar dispuestas a mantener dichas precauciones hasta 2 días después de la última dosis del tratamiento del estudio. Los varones no esterilizados que mantengan relaciones sexuales con mujeres potencialmente fértiles deberán utilizar preservativos más espermicida durante el estudio. Véanse en el Appendix F las directrices al respecto y las definiciones de reproducción y anticoncepción.
    7. Resultados de una prueba de hibridación in situ con fluorescencia (FISH) practicada en el plazo de los 60 días anteriores a la selección que reflejen la presencia o la ausencia de del(17p), 13q del, 11q del y trisomía del cromosoma 12, con el porcentaje de células con la deleción, junto con secuenciación de TP53. Además, los sujetos deberán disponer de un análisis molecular para detección de la mutación IGHV realizado en cualquier momento desde el diagnóstico.
    8. Los sujetos deben estar dispuestos y ser capaces de observar el programa de visitas del estudio, comprender y cumplir con otros requisitos del protocolo y otorgar su consentimiento informado por escrito y autorización para utilizar la información médica protegida.
    E.4Principal exclusion criteria
    1. Participants who have had disease progression while on a BTKi for any malignant or nonmalignant condition.
    2. Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the participant has been disease-free for >= years.
    3. History of confirmed progressive multifocal leukoencephalopathy.
    4. Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia’s formula (QTcF) >480 msec at screening. Note: participants with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
    5. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
    6. Evidence of active Richter's transformation. If Richter’s transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
    7. Central nervous system (CNS) involvement by CLL.
    8. Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with participants who are on ongoing anti-infective treatment and participants who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
    a. Participants who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
    b. Participants who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded.
    9. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
    10. History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
    11. History of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
    12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before Screening.
    13. Major surgical procedure within 4 weeks before first dose of study treatment. Note: Participants who have had major surgery, must have recovered adequately from any
    toxicity and/or complications from the intervention before the first dose of study treatment.
    14. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
    15. All participants requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment except those participants who will be enrolled into the vitamin K antagonist cohort.
    16. Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion.
    17. Total bilirubin >1.5 x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0 x ULN. Exception will be for Gilbert syndrome; if an
    investigator feels that a participants total bilirubin is elevated secondary to Gilbert’s, the participant must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin.
    18. Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement).
    19. Breastfeeding or pregnant.
    1.Sujetos que hayan presentado progresión de la enfermedad durante un tratamiento con BTKi por cualquier proceso, sea o no una neoplasia maligna
    2.Neoplasia maligna previa (distinta de la CLL), excepto el cáncer cutáneo basocelular o espinocelular, carcinoma in situ, cáncer de próstata en fase inicial u otro cáncer, adecuadamente tratados y sin evidencia de enfermedad durante >=2 años
    3.Antecedentes de leucoencefalopatía multifocal progresiva confirmada
    4.Enfermedad cardiovascular importante, como arritmia sintomática, insuficiencia cardiaca congestiva o infarto de miocardio en el plazo de los 6 meses anteriores a la selección, o cualquier cardiopatía de Clase 3 o 4 según la clasificación funcional de la New York Heart Association o intervalo QT corregido con la fórmula de Fridericia (QTcF) >480 ms en la selección.
    5.Síndrome de malabsorción, enfermedad con afectación importante de la función gastrointestinal, resección gástrica, resección amplia del intestino delgado con probable repercusión sobre la absorción, enfermedad inflamatoria intestinal sintomática, obstrucción intestinal parcial o completa, o intervenciones de cirugía bariátrica o restricción gástrica, como la derivación (bypass) gástrica
    6.Evidencia de transformación de Richter activa. En caso de sospecha de transformación de Richter deberá descartarse mediante tomografía por emisión de positrones-tomografía computarizada (PET-CT) y/o biopsia, según las directrices pertinentes
    7.Afectación del sistema nervioso central por la CLL
    8.Antecedentes conocidos de virus de inmunodeficiencia humana, pruebas serológicas indicativas de infección activa por el virus de la hepatitis B o el virus de la hepatitis C, cualquier infección sistémica activa no controlada, así como sujetos en tratamiento antiinfeccioso en curso y sujetos que hayan recibido una vacuna de gérmenes vivos atenuados en el plazo de las 4 semanas anteriores a la primera dosis del tratamiento del estudio
    9.Anemia hemolítica autoinmunitaria o púrpura trombocitopénica idiopática no controladas, definidas como una reducción de la hemoglobina o de la cifra de plaquetas secundaria a destrucción autoinmunitaria durante el periodo de selección o la necesidad de dosis altas de corticosteroides (>20 mg al día de prednisona o equivalente durante más de 2 semanas)
    10.Antecedentes de ictus o hemorragia intracraneal en el plazo de los 6 meses anteriores a la primera dosis del tratamiento del estudio
    11.Antecedentes de diátesis hemorrágica (por ejemplo, hemofilia o enfermedad de von Willebrand)
    12.Presencia de úlcera gastrointestinal diagnosticada por endoscopia en el plazo de los 3 meses anteriores a la selección
    13.Intervención de cirugía mayor en las 4 semanas previas a la primera dosis del tratamiento del estudio. Nota: Los sujetos intervenidos de cirugía mayor deben haberse recuperado adecuadamente de todo efecto secundario y/o complicación de la intervención antes de la primera dosis del tratamiento del estudio.
    14.Necesidad de tratamiento con inhibidores de la bomba de protones (por ejemplo, omeprazol, esomeprazol, lansoprazol, dexlansoprazol, rabeprazol o pantoprazol). Sí podrán participar en este estudio los sujetos en tratamiento con inhibidores de la bomba de protones que se cambien a antagonistas del receptor H2 o a antiácidos.
    15.Necesidad o recepción de tratamiento anticoagulante con warfarina o un antagonista de la vitamina K equivalente (por ejemplo, fenprocumon) en los 7 días previos a la primera dosis del tratamiento del estudio, excepto los sujetos que vayan a entrar en la cohorte de antagonistas de la vitamina K
    16.Cifra absoluta de neutrófilos (absolute neutrophil count, ANC) <0,50 × 109/l o cifra de plaquetas <30 × 109/l, salvo que se demuestre que se deben a la CLL y se eleven por encima de los límites mediante tratamiento con factor estimulante de colonias de granulocitos (G-CSF) y/o transfusión de mezcla de plaquetas
    17.Bilirrubina total >1,5 × límite superior de la normalidad (upper limit of normal, ULN) o aspartato-aminotransferasa alanina-aminotransferasa >3,0 × ULN. El síndrome de Gilbert constituye una excepción; si un investigador considera que la elevación de la bilirrubina total de un sujeto se debe a síndrome de Gilbert, el sujeto deberá mostrar una bilirrubina no conjugada >80% del valor de la bilirrubina total. El investigador también deberá documentar que se ha descartado hemólisis, así como unos valores normales o cercanos a la normalidad de lactato deshidrogenasa y haptoglobina
    18.Aclaramiento de creatinina estimado <30 ml/min, calculado con la fórmula de Cockcroft y Gault o por evaluación directa (es decir, determinación del aclaramiento de creatinina o del aclaramiento de ácido etilendiaminotetraacético)
    19.Lactancia o embarazo
    E.5 End points
    E.5.1Primary end point(s)
    Frequency and relatedness of all AEs, which will also include:
    - Grade >=3 AEs
    - SAEs
    - AEs that lead to discontinuation of treatment
    - ECIs defined as cardiac rhythm disorders, opportunistic infections,interstitial lung disease, major hemorrhage, and cytopenias
    Frecuencia y relación con el tratamiento de todos los acontecimientos adversos, lo que también comprenderá:
    -Acontecimientos adversos de grado >=3
    -Acontecimientos adversos graves
    -Acontecimientos adversos que lleven a la suspensión del tratamiento
    -Acontecimientos de interés clínico, definidos como trastornos del ritmo cardiaco, infecciones oportunistas, enfermedad pulmonar intersticial, hemorragia copiosa y citopenias
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analyses at the study end
    Los análisis finales al final del estudio
    E.5.2Secondary end point(s)
    - ORR (objective response rate)
    - DOR (duration of response)
    - PFS (progression-free survival)
    -Tasa de respuesta objetiva
    -Duración de la respuesta
    -Supervivencia sin progresión
    E.5.2.1Timepoint(s) of evaluation of this end point
    - ORR will be defined as a subject achieving CR, CRi, or PR, according to the IWCLL 2018 criteria as assessed by the investigator.
    - Duration of response (DOR) will be defined as the time from the first objective response of CR, CRi, or PR to the time of documented disease progression or death due to any cause, whichever occurs first.
    - PFS will be defined as the interval from the start of study treatment with study treatment to completion of 48 cycles or the earlier of the first documentation of disease progression or death from any cause.
    -La tasa de respueta objetiva será definida como logro del sujeto por conseguir CR, CRi, o PR, de acuerdo al criterio IWCLL 2018 según el criterio del investigador.
    - La duración de la respuesta será definida como el tiempo desde la primera respuesta objetiva de CR, CRi, o PR hasta el tiempo de progresión de la enfermedad documentada o muerte debida a cualquier causa, cualquiera que ocurra primero.
    - La supervivencia sin progresión será definida como el intervalo desde el inicio del tratamiento del con el tratamiento del estudio hasta la finalización de 48 ciclos o la primera de las documentaciones de la progresión de la enfermedad o muerte por cualquier causa.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. 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 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 concerned8
    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
    Korea, Republic of
    Russian Federation
    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 duration of the study will be approximately 72 months from the first subject enrolled. This duration includes an estimated 24-month recruitment time and an assumed 48 cycles of study treatment (28 days per cycle); additional study time will be accrued during the follow-up period for those subjects remaining on study treatment after completion of 48 cycles (the amount of time will vary by subject).
    La duración del estudio será aproximadamente 72 meses desde el primer sujeto reclutado. Esta duración incluye un reclutamiento estimado de 24 meses y un tratamiento de estudio asumido de 48 ciclos (28 días por ciclo);el tiempo de estudio adicional será acumulado durante el periodo de seguimiento para aquellos sujetos que permanezcan en el tratamiento de estudio después de completar los 48 ciclos (la cantidad de tiempo variará por sujeto).
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 350
    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 Yes
    F. of subjects incapable of giving consent
    Subjects incapable of giving consent for physical or physiological reasons, or reasons linked to their medical condition (e.g. coma, mental disability and in accordance with national requirements)
    Sujetos incapaces de dar consentimiento por razones físicas o psicológicas o razones ligadas a su condición médica (por ejemplo coma, discapacidad mental y de acuerdo a los requerimientos nacionales)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 297
    F.4.2.2In the whole clinical trial 600
    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)
    All subjects will have a Safety Follow-Up (SFU) visit approximately 30 days after the last dose of study treatment. If a subject continues to derive benefit from treatment at the end of 48 cycles, they will continue to be provided with study treatment (for more details please refer to protocol section 4.3)
    Todos los sujetos tendrán una visita de Seguimiento aproximadamente 30 días después de la última dosis de tratamiento del estudio. Si un sujeto continúa recibiendo beneficio del tratamiento al final de los 48 ciclos, se le continuará proporcionando el tratamiento de estudio (para más detalle por favor refierase a la sección 4.3 del protocolo)
    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 Decision2019-09-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-08-30
    P. End of Trial
    P.End of Trial StatusOngoing
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