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    Summary
    EudraCT Number:2017-001551-31
    Sponsor's Protocol Code Number:BGB-3111-304
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-09
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-001551-31
    A.3Full title of the trial
    An International, Phase 3, Open-label, Randomized Study of BGB-3111 Compared with Bendamustine plus Rituximab in Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    Studio internazionale, di fase 3, in aperto, randomizzato di BGB 3111 rispetto a bendamustina più rituximab in pazienti con leucemia linfocitica cronica o piccolo linfoma linfocitico non trattati in precedenza
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study of BGB-3111 Compared with Bendamustine plus Rituximab
    in Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    Studio di fase 3 su BGB-3111 rispetto a bendamustina pi¿ rituximab in pazienti con leucemia linfocitica cronica o piccolo linfoma linfocitico non trattati in precedenza
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberBGB-3111-304
    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 SponsorBEIGENE USA, INC.
    B.1.3.4CountryUnited States
    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 supportBeiGene, Ltd.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBeiGene, Ltd.
    B.5.2Functional name of contact pointUS
    B.5.3 Address:
    B.5.3.1Street AddressUS
    B.5.3.2Town/ cityUS
    B.5.3.3Post codeUS
    B.5.3.4CountryUnited States
    B.5.4Telephone number0
    B.5.5Fax number0
    B.5.6E-mailclinicaltrials@beigene.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 nameBGB-3111
    D.3.2Product code BGB-3111
    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 INNZanubrutinib
    D.3.9.1CAS number 1691249-45-2
    D.3.9.2Current sponsor codeBGB-3111
    D.3.9.4EV Substance CodeSUB184615
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.2.5The 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 nameBendamustine
    D.3.2Product code NA
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 3543-75-7
    D.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB00696MIG
    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.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 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.2.5The 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.3.2Product code NA
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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.3.9.2Current sponsor codeNA
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    Leucemia linfocitica cronica o piccolo linfoma linfocitico non trattati
    E.1.1.1Medical condition in easily understood language
    Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    Leucemia linfocitica cronica o piccolo linfoma linfocitico
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10041152
    E.1.2Term Small lymphocytic lymphoma, consistent with CLL (Working Formulation)
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10003946
    E.1.2Term B-Lymphocytic, CLL (Kiel Classification)
    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 compare efficacy between treatment groups in cohort 1, as measured by progression-free survival determined by independent central review
    Confrontare l¿efficacia tra i gruppi di trattamento della coorte 1, misurata come sopravvivenza libera da progressione determinata mediante revisione centrale indipendente
    E.2.2Secondary objectives of the trial
    To evaluate efficacy in cohort 1, as measured by the following:
    o Overall response rate determined by independent central review and
    by investigator assessment
    o Overall survival
    o Duration of response determined by independent central review and by
    investigator assessment
    o Progression-free survival determined by investigator assessment
    o Patient-reported outcomes
    ¿ To evaluate efficacy in cohort 2 (patients with del17p), as measured
    by the following:
    o Overall response rate determined by independent central review and investigator
    o Overall survival
    o Progression-free survival determined by independent central review
    o Duration of response determined by independent central review
    ¿ To compare safety between the treatment groups in cohort 1
    ¿ To evaluate pharmacokinetics of Zanubrutinib
    ¿ Valutare l¿efficacia nella coorte 1, misurata in base a quanto segue:
    o Tasso di risposta complessiva determinato mediante revisione centrale indipendente e valutazione dello sperimentatore
    o Sopravvivenza complessiva
    o Durata della risposta determinata mediante revisione centrale indipendente e valutazione dello sperimentatore
    o Sopravvivenza libera da progressione determinata mediante valutazione dello sperimentatore
    o Esiti riferiti dal paziente
    ¿ Valutare l¿efficacia nella coorte 2 (pazienti con del17p), misurata in base a quanto segue:
    o Tasso di risposta complessiva determinato mediante revisione centrale indipendente e sperimentatore
    o Sopravvivenza complessiva
    o Sopravvivenza libera da progressione determinata mediante revisione centrale indipendente
    o Durata della risposta determinata mediante revisione centrale indipendente
    ¿ Confrontare la sicurezza tra i gruppi di trattamento della coorte 1
    ¿ Valutare la farmacocinetica di Zanubrutinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patients must be unsuitable for treatment with FCR defined as: = 65 years of age at the time of informed consent, OR 18 - 64 years of age and have one or more of the following factors:
    a. Cumulative Illness Rating Scale (CIRS) score > 6. A CIRS is not required, it may be used to meet this inclusion requirement.
    b. Creatinine clearance < 70 mL/min
    c. History of previous serious infection or multiple infections in the past 2 years
    2. Confirmed diagnosis of CD20-positive CLL or SLL that meets the CLL criteria (Hallek et al, 2008)
    3. Measurable disease by CT/MRI. Measurable disease is defined as = 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters.
    4. CLL/SLL requiring treatment
    5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    6. Life expectancy = 6 months
    7. Adequate bone marrow function
    8. Patient must have adequate organ function
    9. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for = 90 days after the last dose of zanubrutinib, 3 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.
    10. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for = 90 days after the last dose of
    zanubrutinib or 3 months after the last dose of bendamustine whichever is longer.
    11. Ability to provide written informed consent and can understand and comply with the requirements of the study
    1. I pazienti devono avere = 65 anni di età al momento del consenso informato oppure < 65 anni di età ed essere non idonei alla chemioimmunoterapia con fludarabina, ciclofosfamide e rituximab (FCR) in base a 1 o più dei seguenti fattori: punteggio CIRS > 6], clearance della creatinina < 70 ml/min oppure anamnesi di infezione grave e/o di , infezioni multiple precedenti negli ultimi 2 anni
    2. Diagnosi accertata di LLC o SLL positiva per CD-20 che soddisfi i criteri di LLC (Hallek et al., 2008)
    3. Malattia misurabile mediante TC / RM. La malattia misurabile è definita come = 1 linfonodo> 1,5 cm nel diametro più lungo e misurabile in 2 diametri perpendicolari.
    4. CLL/SLL trattamento richiesto
    5. Stato di validità performance del Gruppo cooperativo orientale di oncologia (ECOG) pari a 0, 1 o 2
    6. Aspettativa di vita = 6 mesi
    6. Funzione del midollo osseo adeguata
    7. Il paziente deve avere una funzione organica adeguata
    8. Le pazienti in età fertile devono usare metodi anticoncezionali altamente efficaci, da iniziarsi precedentemente alla prima dose del farmaco in studio, per tutta la durata dello studio, e per = 90 giorni dopo l’ultima dose di Zanubrutinib, 3 mesi dopo l’ultima dose di bendamustina o 12 mesi dopo l’ultima dose di rituximab, in base al periodo più lungo.
    9. I pazienti sono idonei se sottoposti a vasectomia o se accettano di utilizzare un metodo anticoncezionale di barriera con gli altri metodi descritti sopra durante il periodo del trattamento in studio e per = 90 giorni dopo l’ultima dose di Zanubrutinib o 3 mesi dopo l’ultima dose di bendamustina, in base al periodo più lungo.
    10. Capacità di fornire un consenso informato scritto e di comprendere e rispettare i requisiti dello studio.
    E.4Principal exclusion criteria
    1. Previous systemic treatment for CLL/SLL
    2. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped at least 5 days before day of first study drug.
    3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
    4. Clinically significant cardiovascular disease
    5. Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast, or localized Gleason score 6
    prostate cancer.
    6. History of severe bleeding disorder
    7. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
    8. Severe or debilitating pulmonary disease
    9. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic
    inflammatory bowel disease, or partial or complete bowel obstruction
    10. Active fungal, bacterial and/or viral infection requiring systemic therapy
    11. Known central nervous system involvement by leukemia or lymphoma
    12. Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs
    13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection
    14. Major surgery within 4 weeks of the first dose of study drug
    15. Pregnant or lactating women
    16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
    17. Ongoing alcohol or drug addiction
    18. Hypersensitivity to zanubrutinib, bendamustine, or rituximab or any of the other ingredients of the study drugs
    19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
    19. Concurrent participation in another therapeutic clinical trial.
    1. Precedente trattamento sistemico per LLC/SLL
    2. Richiede un bisogno continuo di trattamento con corticosteroidi. NOTA: sistemico i corticosteroidi devono essere completamente rastremati / interrotti almeno 5 giorni prima giorno del primo studio farmaco.
    3. Leucemia prolinfocitica nota o storia di, o attualmente sospettata,
    4. La trasformazione di Richter cardiovascolare clinicamente significativa
    5. Diagnosi di tumore maligno negli ultimi 3 anni, ad eccezione del carcinoma cutaneo a cellule basali o squamose trattato in modo curativo, del tumore superficiale della vescica o del carcinoma in situ della cervice uterina o della mammella o punteggio Gleason localizzato 6 cancro alla prostata.
    6. Anamnesi di disturbo emorragico grave
    6. Anamnesi di ictus o di emorragia intracranica nei 6 mesi precedenti la prima dose del farmaco in studio
    7. Malattia polmonare grave o debilitante
    8. Incapacità di deglutire le capsule o malattia che colpisce notevolmente la funzione gastrointestinale, come la sindrome da malassorbimento, la resezione dello stomaco o dell’intestino tenue, le procedure di chirurgia bariatrica, la malattia infiammatoria intestinale sintomatica, l’ostruzione intestinale parziale o totale
    9. Infezione micotica, batterica e/o virale attiva, che richieda una terapia sistemica
    10. Coinvolgimento noto del sistema nervoso centrale da parte della leucemia o del linfoma
    11. Condizioni mediche sottostanti che, a giudizio dello sperimentatore, renderebbero pericolosa la somministrazione del farmaco in studio o offuscherebbero l’interpretazione della tossicità o degli eventi avversi
    12. Positività per HIV o stato sierologico attestante infezione da epatite B o C attiva
    13. Intervento chirurgico di rilievo entro 4 settimane dalla prima dose del farmaco in studio
    14. Donne in gravidanza o in allattamento
    15. Vaccinazione con un vaccino vivo nei 35 giorni precedenti la prima dose del farmaco in studio
    16. Dipendenza in corso da alcol o droghe
    17. Ipersensibilità a Zanubrutinib, bendamustina o rituximab o a qualsiasi altro ingrediente dei farmaci in studio
    18. Richiede trattamento continuo con un forte inibitore o induttore di CYP3A
    19. Partecipazione simultanea a un’altra sperimentazione clinica terapeutica.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is progression-free survival in cohort 1 (patients without del17p) determined by independent central review using the iwCLL guidelines with modification for treatment-related lymphocytosis in patients with CLL and the Revised Criteria for Response for Malignant Lymphoma in patients with SLL, and defined as the time from
    randomization to the date of first documentation of disease progression or death, whichever occurs first.
    L'endpoint primario è la sopravvivenza libera da progressione nella coorte 1 (pazienti senza del17p) determinato da una revisione centrale indipendente che utilizza il Linee guida iwCLL con modifica per linfocitosi correlata al trattamento in pazienti con CLL e criteri rivisti per risposta per maligna Linfoma in pazienti con SLL e definito come il tempo da randomizzazione alla data della prima documentazione sulla progressione della malattia o morte, a seconda di quale si verifica per primo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 interim analysis of progression-free survival by independent central review in cohort 1, performed when approximately 79 events (67% of the target number of events at final analysis) from the arms A and B are observed. It is estimated that it will take approximately 25 months to observe 79 events. The final analysis of progression-free survival will
    take place after 118 events are observed, which is estimated as approximately 35 months from study start.
    Una analisi intermedia della sopravvivenza libera da progressione tramite esame centrale indipendente nella coorte 1, eseguita quando si sono osservati circa 79 eventi (67% dell’obiettivo del numero di eventi all’analisi finale) nei bracci A e B. Si stima che ci vorranno circa 25 mesi per osservare 79 eventi. L’analisi finale della sopravvivenza libera da progressione avverrà dopo l’osservazione di 118 eventi, stimata a circa 35 mesi dall’inizio dello studio.
    E.5.2Secondary end point(s)
    - Overall response rate in cohort 1 defined as the proportion of patients
    who achieve a complete response, complete response with incomplete
    bone marrow recovery, partial response, or partial response with
    lymphocytosis, determined by independent central review and by
    investigator assessment
    - Overall survival in cohort 1 defined as the time from randomization to
    the date of death due to any reason
    - Duration of response in cohort 1 determined by independent central
    review and by investigator assessment using the iwCLL criteria with
    modification for treatment-related lymphocytosis, and defined as the
    time from the date that response criteria are first met to the date that
    disease progression is objectively documented or death, whichever
    occurs first
    - Progression-free survival in cohort 1 determined by investigator
    assessment
    - Patient-reported outcomes in cohort 1 measured by the EQ-5D-5L and
    EORTC QLQ-C30 questionnaires
    - Overall response rate in cohort 2 (patients with del[17p]) determined
    by independent central review
    - Overall survival in cohort 2
    - Progression-free survival in cohort 2 determined by independent
    central review
    - Duration of response in cohort 2 determined by independent central
    review
    - Safety parameters, including AEs, SAEs, clinical laboratory tests,
    physical exams, and vital signs
    - Pharmacokinetic parameters such as apparent clearance of the drug
    from plasma (CL/F) and AUC0-12
    - Tasso di risposta globale nella coorte 1 definito come la proporzione di pazienti che raggiunge una risposta completa, una risposta completa con recupero incompleto del midollo osseo, una risposta parziale o una risposta parziale con linfocitosi, determinato da un esame centrale indipendente e dalla valutazione dello sperimentatore
    - Sopravvivenza globale nella coorte 1 definita come l¿intervallo di tempo tra la randomizzazione e la data del decesso per qualsiasi causa
    - Durata della risposta nella coorte 1 determinata da un esame centrale indipendente e dalla valutazione dello sperimentatore, utilizzando i criteri iwCLL con la modifica per la linfocitosi connessa al trattamento, e definita come l¿intervallo di tempo tra la data di soddisfazione iniziale dei criteri di risposta e la data in cui - obiettivamente documentata la progressione della malattia o il decesso, in base all¿evento che si verifica per primo.
    - Sopravvivenza libera da progressione nella coorte 1, determinata dalla valutazione dello sperimentatore
    - Esiti riferiti dal paziente nella coorte 1, misurati mediante i questionari EQ-5D-5L e EORTC QLQ-C30
    - Tasso di risposta globale nella coorte 2 (pazienti con del[17p]), determinato da un esame centrale indipendente
    - Sopravvivenza globale nella coorte 2
    - Sopravvivenza libera da progressione nella coorte 2, determinata da un esame centrale indipendente
    - Durata della risposta nella coorte 2, determinata da un esame centrale indipendente
    - Parametri di sicurezza, inclusi eventi avversi, eventi avversi seri, esami clinici di laboratorio, esami obiettivi e segni vitali
    - Parametri farmacocinetici, come la clearance apparente del farmaco dal plasma (CL/F) e AUC0-12
    E.5.2.1Timepoint(s) of evaluation of this end point
    At time of interim analysis if the PFS comparison between the 2 arms in cohort 1 crosses the stopping boundary. Or at the time of final PFS analysis.
    Al momento dell¿analisi intermedia, se il raffronto della PFS tra i 2 bracci nella coorte 1 supera il limite di interruzione. Oppure, al momento dell¿analisi della PFS finale.
    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 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.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 Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA115
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    Czechia
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Russian Federation
    Spain
    Sweden
    Taiwan
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 105
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 445
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 294
    F.4.2.2In the whole clinical trial 550
    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)
    Patients receiving zanubrutinib, who in the opinion of the investigator, continue to benefit from study treatment may continue treatment with zanubrutinib by enrolling on the zanubrutinib Long Term Extension Study.
    I pazienti che ricevono zanubrutinib e che, a giudizio dello sperimentatore, continuano a trarre beneficio dal trattamento in studio, possono continuare il trattamento con zanubrutinib arruolandosi nello Studio di estensione a lungo termine su zanubrutinib.
    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 Decision2018-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-14
    P. End of Trial
    P.End of Trial StatusOngoing
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