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    Summary
    EudraCT Number:2017-001552-54
    Sponsor's Protocol Code Number:BGB-3111-212
    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:2020-11-25
    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 number2017-001552-54
    A.3Full title of the trial
    An International, Phase 2, Open-Label, Randomized Study of BGB-3111
    Combined with Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma
    Studio internazionale di fase 2, in aperto, randomizzato, di BGB-3111 combinato con obinutuzumab rispetto a obinutuzumab in monoterapia nel linfoma follicolare recidivante/refrattario
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study combining BGB-3111 with Obinutuzumab compared with Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma
    Studio di fase 2 di BGB-3111 combinato con obinutuzumab rispetto a obinutuzumab in monoterapia nel linfoma follicolare recidivante/refrattario
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberBGB-3111-212
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03332017
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 pointBeiGene Clinical Support
    B.5.3 Address:
    B.5.3.1Street AddressUSA
    B.5.3.2Town/ cityUSA
    B.5.3.3Post codeUSA
    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.3.9.1CAS 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.2.1.1.1Trade name GAZYVARO
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameObinutuzumab
    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 INNOBINUTUZUMAB
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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
    Relapsed/Refractory Follicular Lymphoma
    Linfoma follicolare recidivante/refrattario
    E.1.1.1Medical condition in easily understood language
    Follicular Lymphoma
    Linfoma follicolare
    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 HLT
    E.1.2Classification code 10016903
    E.1.2Term Follicle centre lymphomas, follicular grade I, II, III
    E.1.2System Organ Class 100000004851
    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 efficacy of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy, as measured by overall response rate determined by independent central review.
    Valutare l’efficacia di Zanubrutinib combinato con
    obinutuzumab rispetto a obinutuzumab in monoterapia, misurata in base al tasso di
    risposta complessiva determinato da una revisione centrale indipendente.
    E.2.2Secondary objectives of the trial
    To evaluate efficacy of zanubrutinib plus obinutuzumab versus
    obinutuzumab monotherapy, as measured by the following:
    -Overall response rate determined by investigator assessment
    -Duration of response determined by independent central review and by
    investigator assessment
    -Progression-free survival determined by independent central review
    and by investigator assessment
    -Overall survival
    -Rate of complete response or complete metabolic response determined
    by independent central review and by investigator assessment
    -Time to response determined by independent central review and by
    investigator assessment
    -Patient-reported outcomes
    • Safety and tolerability
    • Pharmacokinetics (zanubrutinib plus obinutuzumab arm only)
    Valutare l’efficacia di Zanubrutinib combinato con
    obinutuzumab rispetto a obinutuzumab in monoterapia, misurata in base a quanto
    segue:
    • tasso di risposta complessiva determinato dalla valutazione dello sperimentatore;
    • durata della risposta determinata da una revisione centrale indipendente e in base
    alla valutazione dello sperimentatore;
    • sopravvivenza libera da progressione determinata dalla revisione centrale
    indipendente e in base alla valutazione dello sperimentatore;
    • sopravvivenza complessiva;
    • tasso di risposta completa o risposta metabolica completa determinato da una
    revisione centrale indipendente e in base alla valutazione dello sperimentatore;
    • tempo alla risposta determinato da una revisione centrale indipendente e in base alla
    valutazione dello sperimentatore;
    • esiti riferiti dal paziente.
    • Sicurezza e tollerabilità
    • Farmacocinetica (solo per il braccio con Zanubrutinib più obinutuzumab)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -= 18 years of age at the time of informed consent
    -Histologically confirmed diagnosis of B-cell follicular lymphoma (grade
    1, 2 or 3a) based on the WHO 2008 classification of tumors of
    hematopoietic and lymphoid tissue
    -= 2 prior systemic treatments for follicular lymphoma
    -Previously received an anti-CD20 antibody and an appropriate alkylator based combination therapy (such as rituximab, cyclophosphamide,
    doxorubicin, and prednisolone; rituximab, cyclophosphamide, vincristine,
    and prednisolone; or bendamustine plus rituximab)
    -Disease progression within 12 months after completion of most recent
    therapy or refractory disease, defined as failure to achieve CR or PR to
    most recent therapy, and most recent therapy was an appropriate
    second-line (or later) systemic therapy for follicular lymphoma
    -Presence of measurable disease, defined as = 1 nodal lesion that is > 2
    cm in longest diameter, or = 1 extranodal lesion that is > 1 cm in longest
    diameter
    -Availability of archival tissue confirming diagnosis of B-cell follicular
    lymphoma (or if archival tissue is not available, a copy of the pathology
    report confirming diagnosis of B-cell follicular lymphoma is required)
    -Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1,
    or 2
    -Life expectancy = 6 months
    -Adequate organ function defined as:
    a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor
    support within 7 days)
    b. Platelet > 50,000/mm3 (without growth factor support or transfusion
    within 7 days)
    c. Creatinine clearance = 30 ml/min (as estimated by the Cockcroft-
    Gault or MDRD equation or as measured by nuclear medicine scan or 24-
    hour urine collection)
    d. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic
    transaminase, and alanine aminotransferase (ALT)/serum glutamic
    pyruvic transaminase = 3.0 × upper limit of normal (ULN)
    e. Serum total bilirubin < 2.0 × ULN (unless documented Gilbert's
    syndrome)
    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, or 18 months after the last dose of obinutuzumab,
    whichever is longer. Highly effective contraceptive methods include the
    following: a. Combined (estrogen and progestogen containing) hormonal
    contraception associated with the inhibition of ovulation
    i. Oral, intravaginal or transdermal
    b. Progestogen-only hormonal contraception associated with the
    inhibition of ovulation
    i. Oral, injectable, implantable
    c. An intrauterine device
    d. Intrauterine hormone-releasing system
    e. Bilateral tubal occlusion
    f. Vasectomized partner
    g. Sexual abstinence (defined as refraining from heterosexual
    intercourse during the entire period of risk associated with the study
    treatment, starting the day prior to first dose of study drug, for the
    duration of the study, and for = 90 days after the last dose of
    zanubrutinib, or 18 months after the last dose of obinutuzumab,
    whichever is longer). Total sexual abstinence should only be used as a
    contraceptive method if it is in line with the patients' usual and preferred
    lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal,
    post-ovulation methods), declaration of abstinence for the duration of
    exposure to investigational medicinal product, and withdrawal are not
    acceptable methods of contraception.
    Of note, barrier contraception (including male and female condoms with
    or without spermicide) is not considered a highly effective method of
    contraception and if used, this method must be used in combination with
    another acceptable method listed above.
    -Male patients are eligible if vasectomized or if they agree to the use of barrier contraception in combination with other methods described
    above during the study treatment period and for = 90 days after the last
    dose of zanubrutinib.
    see protocol for further criteria
    - età pari o meggiore a 18 anni di età al momento del consenso informato
    - La diagnosi istologicamente confermata del linfoma follicolare delle cellule B (grado
    1, 2 o 3a) sulla base della classificazione WHO 2008 dei tumori al tessuto ematopoietico e linfoide
    - 2 o più trattamenti sistemici precedenti per il linfoma follicolare
    - Precedentemente ricevuto un anticorpo anti-CD20 e un alchilatore appropriato (come
    la rituximab, la ciclofosfamide, doxorubicina e prednisolone; rituximab, ciclofosfamide,
    vincristina, e prednisolone; o bendamustina più rituximab)
    - progressione della malattia entro 12 mesi dal completamento della più recente terapia
    o malattia refrattaria, definita come iil fallimento del raggiungimento CR o PR per la
    terapia più recente, e la terapia più recente è stata un'appropriata terapia sistemica di
    seconda linea (o successiva) per linfoma follicolare
    -Presenza di malattia misurabile, definita come = 1 lesione nodale > 2 cm nel diametro
    più lungo, o = 1 lesione extranodale > 1 cm nel diametro più lungo
    - Disponibilità di tessuti archiviati che confermano la diagnosi di linfoma follicolare delle
    cellule B (o se non sono disponibili, una copia della relazione che conferma la diagnosi
    di linfoma follicolare delle cellule B)
    -Eastern Cooperative Oncology Group (ECOG) pari a 0, 1, o 2
    - aspettativa di vita = 6 mesi
    - Funzione d'organo adeguata definita come:
    a. Conteggio neutrofili assoluto (ANC)> 750 / mm3 (senza supporto di fattori di
    crescita nei 7 giorni)
    b. Piastrine > 50.000 / mm3 (senza supporto di fattori di crescita o trasfusioni nei 7
    giorni)
    c. La clearance della creatinina = 30 ml / min (come stimato dalla equazione di
    Cockcroft-Gault o MDRD o misurata tramite scansione di medicina nucleare o tramite
    raccolta dell'urina nelle 24 ore)
    d. Aspartato aminotransferasi (AST) / siero-glutammico ossalacetico transaminasi, e
    alanina aminotransferasi (ALT) / glutammico siero piruvica transaminasi = 3,0 × limite
    superiore del normale (ULN)
    e. Bilirubina totale del siero <2,0 volte ULN (a meno che non sia documentato la
    sindrome di Gilbert)
    Le pazienti di sesso femminile fertili devono utilizzare un'efficace metodo contraccetivo,
    prima della prima dose di farmaco in studio, per la durata dello studio e per = 90 giorni
    dopo l'ultima dose di Zanubrutinib, o 18 mesi dopo l'ultima dose di obinutuzumab,
    qualunque sia successiva. Questi metodi contraccettivi ad elevata efficacia includono:
    a. Contraccezione ormonale (contenente estrogeno e progesterone) associata
    all'inibizione dell'ovulazione - Orale, intravaginale o transdermica
    b. contraccezione ormonale solo progesterone associata all'inibizione dell'ovulazione -
    Orale, iniettabile, impiantabile
    c. Un dispositivo intrauterino
    d. Sistema di rilascio ormonale intrauterino
    e. Occlusione delle tube bilaterale
    g. L'astinenza sessuale (definita come l'astensione dei rapporti eterosessuali durante
    tutto il periodo di rischio associato al trattamento con il farmaco in studio, iniziando il
    giorno prima della prima dose di farmaco in studio, per la durata dello studio e per =
    90 giorni dopo l'ultima dose di Zanubrutinib, o 18 mesi dopo l'ultima dose di
    obinutuzumab, a seconda di quale sia successiva).
    L'astinenza sessuale totale dovrebbe essere utilizzata solo come metodo contraccettivo
    se è in linea con lo stile di vita abituale e preferito dei pazienti. L'astinenza periodica
    (ad es. metodi del calendario, ovulazione, simptotermica, post-ovulazione),
    dichiarazione di astinenza per la durata dell'esposizione al farmaco in studio e il ritiro
    non sono metodi accettabili di contraccezione. Da notare, la contraccezione di barriera
    (compresi i preservativi maschili e femminili con o senza spermicida) non è considerata
    un metodo molto efficace di contraccezione e se usato, questo metodo deve essere
    utilizzato in combinazione con un altro metodo accettabile elencato in precedenza.
    fare riferimento al protocollo per altri criteri
    E.4Principal exclusion criteria
    Each patient eligible to participate in this study must NOT meet any of
    the following exclusion criteria:
    1. Known central nervous system involvement by leukemia or lymphoma
    2. evidence of transformation from follicular lymphoma to DLBCL or
    other aggressive histology (such as large cells seen on biopsy or high
    PET avidity in a single node seen on PET scan)
    3. Allogeneic hematopoietic stem cell transplantation within 12 months
    of study enrollment
    4. Prior exposure to a BTK inhibitor
    5. Prior malignancy within the past 5 years, except for curatively treated
    basal or squamous cell skin cancer, superficial bladder cancer, carcinoma
    in situ of the cervix or breast, or localized Gleason score 6 prostate
    cancer.
    6. Clinically significant cardiovascular disease including the following:
    a. Myocardial infarction within 6 months before screening
    b. Unstable angina within 3 months before screening
    c. New York Heart Association class III or IV congestive heart failure
    (See Appendix 4)
    d. History of clinically significant arrhythmias (eg, sustained ventricular
    tachycardia, ventricular fibrillation, torsades de pointes)
    e. QTcF > 480 msecs based on Fridericia's formula
    f. History of Mobitz II second-degree or third degree heart block without
    a permanent pacemaker in place
    g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive
    blood pressure measurements showing systolic blood pressure > 170
    mm Hg and diastolic blood pressure > 105 mm Hg at screening
    7. History of severe bleeding disorder such as hemophilia A, hemophilia
    B, von Willebrand disease, or history of spontaneous bleeding requiring
    blood transfusion or other medical intervention
    8. History of stroke or intracranial hemorrhage within 6 months before
    first dose of study drug
    9. Severe or debilitating pulmonary disease
    10. 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
    11. Active fungal, bacterial and/or viral infection requiring systemic
    therapy 12. Underlying medical conditions that, in the investigator's opinion, will
    render the administration of study drug hazardous or obscure the
    interpretation of safety or efficacy results
    13. Known infection with HIV, or serologic status reflecting active
    hepatitis B or C infection as follows:
    a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core
    antibody (HBcAb). Patients with presence of HBcAb, but absence of
    HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20
    IU/mL), and if they are willing to undergo monthly monitoring for HBV
    reactivation.
    b. Presence of hepatitis C virus (HCV) antibody. Patients with presence
    of HCV antibody are eligible if HCV RNA is undetectable (<15 IU/mL).
    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 or obinutuzumab or any of the other
    ingredients of the study drugs
    19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
    20. Concurrent participation in another therapeutic clinical trial.
    Ogni paziente eleggibile per questo studio NON deve soddisfare nessuno dei seguenti criteri di esclusione:
    1. Compromissione nota del sistema nervoso centrale per leucemia o linfoma
    2. Nessuna evidenza di trasformazione da linfoma follicolare a DLBCL o altre istologie aggressive (come le cellule grandi viste in biopsia o tramite PET in un singolo nodo)
    3. Trapianto allogenico di cellule staminali ematopoietiche entro 12 mesi dall'arruolamento
    4. Esposizione precedente ad un inibitore BTK
    5. precedente lesione maligna negli ultimi 5 anni, ad eccezione del cancro della pelle delle cellule basali o squamose, della vescica superficiale, il carcinoma
    in situ della cervice o del seno, o cancro della prostata localizzato Gleason score 6
    6. Malattia cardiovascolare clinicamente significativa comprendente:
    a. Infarto miocardico entro 6 mesi prima dello screening
    b. Angina instabile entro 3 mesi prima dello screening
    c. Insufficienza cardiaca congestizia di classe III o IV della New York Heart Association (Vedi appendice 4)
    d. Storia di aritmie clinicamente significative (es. Ventricolo sostenuto, tachicardia, fibrillazione ventricolare, torsades de pointes)
    e. QTcF> 480 msecs sulla base della formula di Fridericia
    f. Storia del blocco cardiaco di secondo grado o di terzo grado secondo Mobitz II senza un pacemaker permanente in atto
    g. Ipertensione non controllata come indicato da un minimo di 2 consecutive misurazioni di pressione sanguigna che mostrano pressione sanguigna sistolica> 170 mm Hg e pressione diastolica> 105 mm Hg allo screening
    7. Storia di disturbi sanguigni gravi quali emofilia A, emofilia B, la malattia di von Willebrand, o episodi di sanguinamento spontaneo che richiedono
    trasfusione di sangue o altro intervento medico
    8. precedenti ictus o emorragie intracraniche nei 6 mesi precedenti l prima dose di farmaco in studio
    9. Malattia polmonare grave o debilitante
    10. Incapacità a ingoiare capsule o malattie che interessano significativamente la funzionalità gastrointestinale come la sindrome di malassorbimento, resezione dello stomaco o dell'intestino, procedure di chirurgia bariatrica, malattia intestinale infiammatoria sintomatica o ostruzione parziale o completa dell'intestino
    11. Infezione fungina attiva, batterica e / o virale che richiede une terapia sistemica
    12. Sottostanti condizioni mediche che, secondo il ricercatore, possono rendere la somministrazione del farmaco in studio pericolosa o impedire l'interpretazione dei risultati di sicurezza o di efficacia
    13. Infezione nota da HIV, o stato sierologico che riflette infezione attiva da epatite B o C come segue:
    a. Presenza di antigene superficiale dell'epatite B (HBsAg) o anticorpo core dell'epatite B
    (HBcAb). Pazienti con presenza di HBcAb, ma assenza di HBsAg, sono arruolabili se il DNA del virus dell'epatite B (HBV) non è rilevabile (<20
    IU / mL) e se sono disposti a sottoporsi a monitoraggio mensile per la riattivazione di HBV .
    b. Presenza di anticorpi anti-epatite C (HCV). Pazienti con presenza di anticorpo HCV sono arruolabili se l'HCV RNA non è rilevabile (<15 UI / mL).
    14. intervento chirurgico importante nelle 4 settimane prima della prima dose di farmaco in studio.
    15. donne incinte o che allattano
    16. Vaccinazione con un vaccino vivo entro 35 giorni prima della prima dose di farmaco in studio
    17. Alcool o tossicodipendenza in corso
    18. Ipersensibilità a Zanubrutinib o obinutuzumab o ad uno qualsiasi degli componenti del farmaco in studio
    19 è in corso un necessario trattamento con un forte inibitore o induttore di CYP3A
    20. Partecipazione contemporanea ad un altro studio clinico terapeutico.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is overall response rate determined by independent central review using Lugano Classification for Non-Hodgkin
    Lymphoma (NHL), (modified from Cheson et al, 2014). The overall response rate is defined as the proportion of patients who achieve either
    complete response or partial response as best overall response. Best overall response is defined as best response achieved during the entire
    follow-up period. However, for the patients in arm B who cross over to arm A, the disease assessment after the crossover will not be included in the derivation of best overall response.
    L’endpoint primario è il tasso di risposta complessiva determinato da una revisione centrale indipendente, che utilizza la Classificazione di Lugano per il linfoma non Hodgkin (LNH) (modificato da Cheson et al, 2014). La risposta complessiva è definita come la percentuale dei pazienti che conseguono una
    risposta completa o risposta parziale come migliore risposta globale. La migliore risposta complessiva è definita come risposta migliore raggiunta durante l'intero periodo di follow-up. Tuttavia, per i pazienti nel braccio B che passano al braccio A, la valutazione della malattia dopo il crossover non sarà inclusa nella derivazione della migliore risposta globale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 12 weeks for 24 months, then every 6 months for 24 months, then annually.
    Ogni 12 settimane per 24 mesi, poi ogni 6 mesi per 24 mesi, poi annualmente
    E.5.2Secondary end point(s)
    Overall response rate determined by investigator assessment
    ¿ Duration of response determined by independent central review and by
    investigator assessment, 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 determined by independent central review
    and by investigator assessment, defined as the time from randomization
    to the date of first documentation of disease progression or death,
    whichever occurs first
    ¿ Overall survival defined as the time from randomization to the date of
    death due to any reason.
    ¿ Rate of complete response or complete metabolic rate determined by
    independent central review and by investigator assessment, defined as
    the proportion of patients who achieve complete response or complete
    metabolic rate as best overall response
    ¿ Time-to-response determined by independent central review and by
    investigator assessment, defined as the time from randomization to the
    time the response criteria are first met
    Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L
    questionnaires
    ¿ Safety parameters, including AEs, SAEs, clinical laboratory tests,
    physical exams, and vital signs
    ¿ PK parameters such as apparent clearance of the drug from plasma
    (CL/F) and AUC0-12
    Tasso totale di risposta determinato dalla valutazione dello sperimentatore
    ¿ durata della risposta determinata dalla revisione centrale indipendente e dallo sperimentatore, definita come il tempo dalla data in cui i criteri di risposta vengono soddisfatti alla data in cui la progressione della malattia ¿ documentata obiettivamente o la data della morte, a seconda di quale si verifica prima
    ¿ sopravvivenza senza progressione determinata dalla revisione centrale indipendente
    e dallo sperimentatore, definito come il tempo dalla randomizzazione alla data della prima documentata progressione della malattia o della morte,
    a seconda di quale si verifica prima
    ¿ Sopravvivenza globale definita come il tempo dalla randomizzazione alla data di morte per qualsiasi ragione.
    ¿ tasso di risposta completa o risposta metabolica completa determinato da una revisione centrale indipendente e in base alla valutazione dello sperimentatore, definita come la percentuale di pazienti che hanno una risposta completa o una risposta metabolica completa come migliore risposta globale
    ¿ Tempo di risposta determinato dalla revisione centrale indipendente e dallo sperimentatore, definito come il tempo dalla randomizzazione al
    tempo i criteri di risposta sono per la prima volta soddisfatti
    Risultati dei pazienti misurati tramite questionari EORTC QLQ-C30 e EQ-5D-5L
    ¿ I parametri di sicurezza, tra cui AEs, SAEs, test clinici di laboratorio, esami fisici e segni vitali
    ¿ i parametri PK come la clearance apparente del farmaco nel plasma (CL / F) e AUC0-12
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 12 weeks for 24 months, then every 6 months for 24 months, then annually.
    Ogni 12 settimane per 24 mesi, poi ogni 6 mesi per 24 mesi, poi annualmente
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA58
    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
    Belarus
    Bulgaria
    Canada
    Czechia
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    New Zealand
    Poland
    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 years4
    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 years4
    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: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 140
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 123
    F.4.2.2In the whole clinical trial 210
    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 assigned to arm A (zanubrutinib plus obinutuzumab), 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;this is a rollover study for
    patients who wish to continue receiving zanubrutinib.
    I pazienti assegnati al
    braccio A (Zanubrutinib in combinazione con obinutuzumab), che secondo il parere dello
    sperimentatore continuano a beneficiare del trattamento in studio, possono continuare il
    trattamento con Zanubrutinib arruolandosi nel Zanubrutinib Long Term Extension Study,
    uno studio di rollover per i pazienti che desiderano continuare a ricevere 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 Decision2018-01-19
    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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