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    Summary
    EudraCT Number:2018-002443-28
    Sponsor's Protocol Code Number:ACE-CL-311/D8221C00001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2019-01-24
    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 number2018-002443-28
    A.3Full title of the trial
    A Randomized, Multicenter, Open-Label, Phase 3 Study to Compare the Efficacy and Safety of Acalabrutinib (ACP-196) in Combination with Venetoclax with and without Obinutuzumab Compared to Investigator’s Choice of Chemoimmunotherapy in Subjects with Previously Untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation
    Ensayo fase 3, aleatorizado, multicéntrico y abierto para comparar la eficacia y seguridad de acalabrutinib (ACP-196) en combinación con venetoclax con y sin obinutuzumab, con la eficacia y seguridad de la quimioinmunoterapia elegida por el investigador en pacientes con leucemia linfocítica crónica sin mutación del(17p) o TP53, no tratada previamente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study is being done to test the effectiveness and safety of an investigational drug called acalabrutinib (ACP-196) when taken with already marketed drugs called Venetoclax and Obinutzumab in comparison to chemotherapy that is already in wide use for treatment of patients who have chronic lymphocytic leukemia and who have never been treated before.
    Este estudio se está realizando para comprobar la efectividad y seguridad de un medicamento en investigación llamado acalabrutinib (ACP-196) cuando se toma con medicamentos ya comercializados llamados Venetoclax y Obinutzumab en comparación con la quimioterapia que ya se usa ampliamente para el tratamiento de pacientes con Leucemia linfocítica crónica y que nunca antes han sido tratados.
    A.3.2Name or abbreviated title of the trial where available
    Not available at this time
    No disponible aún
    A.4.1Sponsor's protocol code numberACE-CL-311/D8221C00001
    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 SponsorAcerta Pharma B.V.
    B.1.3.4CountryNetherlands
    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
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcerta Pharma B.V.
    B.5.2Functional name of contact pointCheng Quah, Medical Director
    B.5.3 Address:
    B.5.3.1Street Address121 Oyster Point Blvd
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number16505912800
    B.5.6E-mailcheng.quah@acerta-pharma.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 Yes
    D.2.5.1Orphan drug designation numberEMA/OD/196/15
    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.3.9.4EV Substance CodeSUB182073
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Gazyvaro
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNobinutuzumab
    D.3.9.1CAS number 949142-50-1
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 Yes
    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: 3
    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.2.1.2Country 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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed 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/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number375, 500
    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 Yes
    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: 4
    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.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for injection/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 INNcyclophosphamide monohydrate
    D.3.9.1CAS number 50-18-0
    D.3.9.3Other descriptive nameCYCLOPHOSPHAMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB16414MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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: 5
    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.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    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 INNFLUDARABINE
    D.3.9.1CAS number 21679-14-1
    D.3.9.4EV Substance CodeSUB07678MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Venclyxto
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Deutschland GmbH & Co.KG
    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.3.4Pharmaceutical form Coated tablet
    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 INNVENETOCLAX
    D.3.9.1CAS number 1257044-40-8
    D.3.9.4EV Substance CodeSUB176260
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    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.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    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 INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 16506-27-7
    D.3.9.4EV Substance CodeSUB00696MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/m2 milligram(s)/square meter
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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
    Previously untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation
    Leucemia linfocítica crónica sin mutación del (17p) o TP53 sin tratamiento previo
    E.1.1.1Medical condition in easily understood language
    Previously untreated low-risk blood cancer
    Cáncer de sangre de bajo riesgo no tratado previamente
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10009310
    E.1.2Term CLL
    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 efficacy of acalabrutinib/venetoclax (AV; Arm A) compared with chemoimmunotherapy
    (fludarabine/cyclophosphamide/rituximab [FCR]/ bendamustine/rituximab [BR]; Arm C)
    Evaluar la eficacia de acalabrutinib/venetoclax (AV; grupo A) en comparación con quimioinmunoterapia (fludarabina/ ciclofosfamida/ rituximab [FCR] / bendamustina/ rituximab [BR]; grupo C)
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of acalabrutinib/venetoclax/obinutuzumab (AVG; Arm B) versus FCR/BR (Arm C)

    To evaluate the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B) versus FCR/BR (Arm C)
    Evaluar la eficacia de acalabrutinib/ venetoclax/ obinutuzumab (AVG; grupo B) en comparación con FCR/BR (grupo C)
    Evaluar la eficacia de AV (grupo A) en comparación con FCR/BR (grupo C) y de AVG (grupo B) en comparación con FCR/BR (grupo C)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Men and women ≥18 years of age.
    2.Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
    3.Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):
    Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing B-cell marker (CD19, CD20, and CD23) and CD5.
    Prolymphocytes may comprise <55% of blood lymphocytes.
    Presence of ≥5x109 B lymphocytes/L (5000/µL) in the peripheral blood (at any point since the initial diagnosis).
    4.Active disease per IWCLL 2018 criteria that requires treatment (see Section 4.5.6).
    5.Meet the following laboratory parameters:
    a) Adequate bone marrow function independent of growth factor or transfusion support within 1 week of Screening, as follows:
    i.ANC ≥750 cells/μL (0.75x109/L); ANC ≥500 cells/μL (0.50x109/L) in subjects with documented bone marrow involvement of CLL
    ii.Platelet count ≥50,000 cells/μL (50x109/L); platelet count ≥30,000 cells/μL (30x109/L) in subjects with documented bone marrow involvement of CLL
    b)Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5xULN.
    c)Total bilirubin ≤2xULN, unless directly attributable to Gilbert’s syndrome
    d)Estimated creatinine clearance of ≥50 mL/min, calculated using the formula of Cockcroft and Gault (if male, [140Age] x Mass (kg) / [72 x creatinine mg/dL]; multiply by 0.85 if female); estimated creatinine clearance of ≥70 mL/min for subjects selected by investigator to receive FCR in Arm C
    1.Varones y mujeres de 18 años o más de edad.
    2.Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0-2.
    3.Diagnóstico de LLC que cumpla los criterios diagnósticos publicados (Hallek et al. 2018):
    Linfocitos B monoclonales (con restricción de cadenas ligeras kappa o lambda) con coexpresión clonal de marcadores de linfocitos B (CD19, CD20 y CD23) y CD5.
    Los prolinfocitos podrán suponer < 55 % de los linfocitos sanguíneos.
    Presencia de ≥ 5 x 109 linfocitos B/l (5000/µl) en sangre periférica (en cualquier momento desde el diagnóstico inicial).
    4.Enfermedad activa según los criterios IWCLL 2018 que requiere tratamiento (véase la Sección 4.5.6).
    5.Cumplimiento de los siguientes parámetros analíticos:
    a.Función medular adecuada con independencia del apoyo con factores de crecimiento o transfusiones en la semana previa a la selección, tal como sigue:
    i.RAN ≥ 750 células/µl (0,75 x 109/l); RAN ≥ 500 células/µl (0,50 x 109/l) en pacientes con afectación documentada de la médula ósea por la LLC.
    ii.Recuento de plaquetas ≥ 50.000 células/µl (50 x 109/l); recuento de plaquetas ≥ 30.000 células/µl (30 x 109/l) en pacientes con afectación documentada de la médula ósea por la LLC.
    b.Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) en suero ≤ 2,5 veces el LSN.
    c.Bilirrubina total ≤ 2 veces el LSN, a menos que sea atribuible directamente a un síndrome de Gilbert.
    d.Aclaramiento de creatinina estimado ≥ 50 ml/min, calculado con la fórmula de Cockcroft y Gault (en caso de ser varón, [140 x edad] x masa (kg) / [72 x creatinina mg/dl]; multiplicado por 0,85 en caso de ser mujer); aclaramiento de creatinina estimado ≥ 70 ml/min en los pacientes seleccionados por el investigador para recibir FCR en el grupo C.
    E.4Principal exclusion criteria
    •Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisone daily are permitted).
    •Detected del(17p) or TP53 mutation.
    •Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter’s transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia.
    •Any comorbidity or organ system impairment rated with a single CIRS score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), or a total CIRS score of >6.
    •Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
    •History of confirmed progressive multifocal leukoencephalopathy (PML).
    •Received any investigational drug within 30 days before first dose of study drug.
    •Major surgical procedure within 30 days before the first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
    •History of prior malignancy that could affect compliance with the protocol, or interpretation of results, except for the following:
    •Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study.
    •Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for ≥3 years without further treatment.
    •Cualquier tratamiento previo específico para la LLC (excepto el tratamiento con corticosteroides administrado por una intervención inmediata necesaria; en los 10 días previos al comienzo del tratamiento del ensayo solo se permitirá la administración de equivalentes de dosis de hasta 20 mg de prednisona al día).
    •Mutación del(17p) o TP53 detectada.
    •Transformación de la LLC en un linfoma no hodgkiniano (LNH) agresivo (por ejemplo, transformación de Richter, leucemia prolinfocítica [LPL] o linfoma difuso de linfocitos B grandes [LDLBG]) o afectación del sistema nervioso central (SNC) por la leucemia.
    •Cualquier comorbilidad o deterioro de un sistema orgánico valorado con una puntuación CIRS (Escala de valoración acumulada de enfermedades) única de 4 (excluido el sistema orgánico de ojos, oídos, nariz, garganta y laringe) o una puntuación CIRS total > 6.
    •Anemia hemolítica autoinmunitaria o púrpura trombocitopénica idiopática no controlada.
    •Antecedentes de leucoencefalopatía multifocal progresiva (LMP) confirmada.
    •Recepción de cualquier fármaco en investigación en los 30 días previos a la primera dosis del fármaco del ensayo.
    •Intervención de cirugía mayor en los 30 días previos a la primera dosis del fármaco del ensayo. Nota: Si un paciente se ha sometido a una intervención de cirugía mayor, deberá haberse recuperado debidamente de cualquier toxicidad o complicación de la intervención antes de la primera dosis del fármaco del ensayo.
    •Antecedentes de una neoplasia maligna previa que pueda afectar al cumplimiento del protocolo o a la interpretación de los resultados, excepto lo siguiente:
    •Carcinoma basocelular o espinocelular de piel tratado con intención curativa o carcinoma in situ de cuello uterino o carcinoma de próstata in situ en cualquier momento antes del ensayo.
    •Otros cánceres no especificados anteriormente que hayan sido tratados con intención curativa mediante cirugía, radioterapia o ambas, de los que el paciente haya permanecido sin enfermedad durante ≥ 3 años sin más tratamiento.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria.
    Supervivencia sin progresión (SSP), definida como el tiempo transcurrido entre la aleatorización y el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra antes), según lo determinado por el comité de revisión independiente (CRI) conforme a los criterios IWCLL (International Workshop on ChronicLymphocytic Leukemia) 2018.
    E.5.1.1Timepoint(s) of evaluation of this end point
    64 months
    64 meses
    E.5.2Secondary end point(s)
    1.PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment according to the IWCLL 2018 criteria.
    2.Overall response rate (ORR), defined as the proportion of subjects with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) per the investigator and IRC assessment as per IWCLL 2018 criteria
    3.Duration of objective response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause per the investigator and IRC assessment as per IWCLL 2018 criteria
    4.Time to next Therapy (TTNT), defined as the time from randomization to institution of non-protocol specified treatment for chronic lymphocytic leukemia (CLL)
    5.Minimal residual disease (MRD) negativity rate (determined as the proportion of subjects with MRD-negativity) measured in the peripheral blood by flow cytometry (10-4) at the start of Cycle 9 (in Arm A), the start of Cycle 10 (in Arm B), and 12 weeks after the start of Cycle 6 (in Arm C)
    6.Overall survival (OS), defined as the time from randomization to death from any cause
    1.SSP, definida como el tiempo transcurrido entre la aleatorización y el primer episodio de progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra antes), según lo determinado por el CRI conforme a los criterios IWCLL 2018
    2.Tasa de respuesta global (TRG), definida como la proporción de pacientes con una respuesta completa (RC), respuesta completa con recuperación incompleta de la médula ósea (RCi) o respuesta parcial (RP) según la evaluación del investigador y del CRI conforme a los criterios IWCLL 2018.
    3.Duración de la respuesta objetiva (DRO), definida como el tiempo transcurrido entre el primer episodio de una respuesta objetiva documentada y la progresión de la enfermedad o la muerte por cualquier causa, según la evaluación del investigador y del CRI conforme a los criterios IWCLL 2018.
    4.Tiempo hasta el siguiente tratamiento (THST), definido como el tiempo transcurrido entre la aleatorización y la instauración de un tratamiento no especificado en el protocolo para la leucemia linfocítica crónica (LLC).
    5.Tasa de negatividad de enfermedad residual mínima (ERM) (determinada como la proporción de pacientes con negatividad de ERM) medida en sangre periférica mediante citometría de flujo (10-4) al comienzo del ciclo 9 (en el grupo A), al comienzo del ciclo 10 (en el grupo B) y 12 semanas después del comienzo del ciclo 6 (en el grupo C).
    6.Supervivencia global (SG), definida como el tiempo transcurrido entre la aleatorización y la muerte por cualquier causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    64 months
    64 meses
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    health status, biomarkers
    Estado de salud, biomarcadores
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.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 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 Yes
    E.8.2.3.1Comparator description
    FCR/BR
    FCR/BR
    E.8.2.4Number of treatment arms in the trial3
    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 EEA105
    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
    Canada
    China
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Democratic People's Republic of
    Netherlands
    New Zealand
    Poland
    Saudi Arabia
    South Africa
    Spain
    Sweden
    Taiwan
    Turkey
    Ukraine
    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
    The end of study is defined as approximately 5 years after the last subject is randomized in the study (unless all subjects have died). The approximate length of the study will be 7 years calculated from an estimated 24-month recruitment period.
    El final del estudio se define como aproximadamente 5 años después de que el último sujeto sea randomizado en el estudio (a menos que todos los sujetos hayan fallecido). La duración aproximada del estudio será de 7 años calculada a partir de un período de reclutamiento estimado de 24 meses
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years7
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 500
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 780
    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)
    The sponsor will offer post-study access to acalabrutinib free of charge in accordance with the AstraZeneca Global Policy on Early Access to IMP. Subject must meet all of the following eligibility criteria:
    •The subject is suffering from a serious or life-threatening disease and has exhausted all available therapeutic options.
    •medical status is deemed appropriate to receive the study drug.
    •must be able to routinely travel to the clinic site for monitoring and follow up as required.
    Sponsor ofrecerá acceso al post-estudio de acalabrutinib gratuitamente de acuerdo con la Política global de AZ sobre acceso temprano a IMP. El sujeto debe cumplir todos los siguientes criterios de elegibilidad:
    • padecer enfermedad grave o potencialmente mortal y haber agotado todas opciones terapéuticas disponibles.
    • estado médico considerado apropiado para recibir el medicamento del estudio.
    • capaz de viajar rutinariamente a sitio clínico para monitorización y seguimiento según necesidad.
    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 Decision2019-05-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-11
    P. End of Trial
    P.End of Trial StatusRestarted
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