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    Summary
    EudraCT Number:2016-002980-33
    Sponsor's Protocol Code Number:BGB-3111-302
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-06-02
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2016-002980-33
    A.3Full title of the trial
    A Phase 3, Randomized, Open-Label, Multicenter Study
    Comparing the Efficacy and Safety of the Bruton’s Tyrosine
    Kinase (BTK) Inhibitors BGB-3111 and Ibrutinib in Subjects
    with Waldenström’s Macroglobulinemia (WM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, Randomized, Open-Label, Multicenter Study Comparing the Efficacy and Safety of the medications BGB-3111 and Ibrutinib in Subjects with Waldenström’s Macroglobulinemia (WM)
    A.4.1Sponsor's protocol code numberBGB-3111-302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03053440
    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 Ltd. c/o BeiGene 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 USA, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBeiGene USA, Inc.
    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.5.6E-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 namezanubrutinib (BGB-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 INNnot yet established
    D.3.9.1CAS number 1691249-45-2
    D.3.9.2Current sponsor codeBGB-3111
    D.3.9.3Other descriptive namePH-BEI-BGB-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 No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imbruvica
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    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 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 INNibrutinib
    D.3.9.1CAS number 936563-96-1
    D.3.9.3Other descriptive nameIBRUTINIB
    D.3.9.4EV Substance CodeSUB120863
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number140
    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
    Subjects with Waldenström’s Macroglobulinemia (WM) who require therapy according to the consensus panel criteria from the 7th International Workshop on Waldenström’s Macroglobulinemia
    E.1.1.1Medical condition in easily understood language
    Patients with Waldenström’s Macroglobulinemia (WM)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10047801
    E.1.2Term Waldenstrom's macroglobulinaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of zanubrutinib (BGB-3111) vs ibrutinib in subjects with MYD88MUT WM
    E.2.2Secondary objectives of the trial
    To further compare the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib (BGB-3111) vs ibrutinib in subjects with MYD88MUT WM.

    To evaluate safety and tolerability of zanubrutinib (BGB-3111) versus ibrutinib in subjects with MYD88MUT WM, as measured by the incidence and severity of adverse events
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Clinical and definitive histologic diagnosis of WM.Subjects must either have relapsed/refractory disease OR be treatment naïve and considered by their treating physician to be unsuitable for standard
    chemoimmunotherapy regimens.
    a. For subjects who have received no prior therapy for WM: "Unsuitable" for treatment with a standard chemoimmunotherapy regimen must be a physician-determined status based on co-morbidities and risk factors. Physicians will need to provide and document organ system(s) and specific reason(s) for subject being considered unsuitable. Patient preference does not meet the eligibility requirement for a
    treatmentnaïve subject to be unsuitable for treatment with a standard chemoimmunotherapy regimen.
    2. Meeting at least one criterion for treatment according to consensus panel criteria from the Seventh IWWM (Dimopoulos et al 2014)
    3. Measurable disease, as defined by serum IgM level >0.5 g/dL
    4. Age ≥ 18 years old
    5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
    6. Adequate bone marrow function defined as:
    - Neutrophils ≥ 0.75 x 10 power 9/L independent of growth factor support within 7 days of study entry
    - Platelets ≥ 50 x 10 power 9/L, independent of growth factor support or transfusion within 7 days of study entry
    7. Creatinine clearance of ≥ 30 ml/min (as estimated by the CockcroftGault equation or estimated glomerular filtration rate [eGFR] from the Modification of Diet in Renal Disease [MDRD])based on ideal body mass.
    11. Subjects who relapse after autologous stem cell transplant are eligible if they are at least 3 months after transplant, and are eligible after allogeneic transplant if they are at least 6 months post-transplant. To be eligible after either type of transplant, subjects should have no active infections or in the case of allogeneic transplant relapse, no active acute graft versus host disease (GvHD) of any grade, and no chronic
    GvHD other than mild skin, oral, or ocular GvHD not requiring systemic immunosuppression.
    E.4Principal exclusion criteria
    1. Prior exposure to a BTK inhibitor.
    2. Evidence of disease transformation at the time of study entry.
    3. Corticosteroids given with antineoplastic intent within 7 days, or chemotherapy, targeted therapy, or radiation therapy within 3 weeks, or antibody-based therapy within 4 weeks of the start of study drug.
    4. Major surgery within 4 weeks of study treatment.
    5. Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, absolute neutrophil count [ANC] and platelets). For ANC and platelets, please follow inclusion criteria #6 [neutrophils] and [platelets]).
    6. History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous
    malignancy confined and treated locally (surgery or other modality) with curative intent.
    7. Currently active, clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease (congestive heart failure) as defined by the New York
    Heart Association (NYHA) Functional Classification, or history of myocardial infarction within 6 months of screening.
    8. QTcF prolongation (defined as a QTcF > 480 msec)
    9. Active, clinically significant Electrocardiogram (ECG) abnormalities including second degree atrioventricular (AV) block Type II, or third degree AV block.
    10. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease,
    or partial or complete bowel obstruction.
    11. Uncontrolled active systemic infection or recent infection requiring parenteral anti-microbial therapy that was completed ≤14 days before the first dose of study drug.
    12. Known infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or hepatitis C as follows:
    a) Presence of hepatitis B surface antigen (HbsAg) or anti-hepatitis core antibody (anti-HBc). Patients with presence of anti-HBc, but absence of HBsAg are eligible if hepatitis B virus (HBV) DNA is undetectable and if
    they are willing to undergo monthly monitoring for HBV reactivationb).
    b) Presence of hepatitis C virus (HCV] antibody. Patients with presence of HCV antibody are eligible if HCV ribonucleic acid (RNA) is undetectable.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of subjects in Cohort 1 achieving either CR or VGPR, as determined by independent review committee (IRC) using an adaptation of the response criteria updated at the Sixth IWWM (Owen et al. 2013 and NCCN Guidelines, Lymphoplasmacytic
    Lymphoma/Waldenström’s Macroglobulinemia 2015: v2).
    E.5.1.1Timepoint(s) of evaluation of this end point
    As determined by independent review committee (IRC).
    E.5.2Secondary end point(s)
    - Major response rate (MRR) as assessed by the IRC, defined as the proportion of subjects achieving CR, VGPR, or partial response (PR)
    - Duration of response (DOR) as assessed by the IRC, defined as the time from first determination of response (CR, VGPR or PR) (per modified IWWM criteria) until first documentation of progression (per modified IWWM criteria) or death, whichever comes first
    - Rate of CR or VGPR as assessed by the Investigator
    - DOR as assessed by the Investigator, defined as the time from first determination of response (CR, VGPR or of PR) (per modified IWWM criteria) until first documentation of progression (per modified IWWM criteria) or death, whichever comes first
    - Progression-free survival (PFS) as assessed by the IRC, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first
    - PFS as assessed by the Investigator, defined as time from randomization to the first documentation of progression (per modified IWWM criteria) or death, whichever occurs first
    - Resolution of treatment-precipitating symptoms, defined as the absence of the symptoms that triggered initiation of study treatment (per the IWWM treatment guidelines) at any point during study treatment

    - Anti-lymphoma effect, defined as any reduction in bone marrow involvement by lymphoplasmacytoid lymphocytes and/or size of lymphadenopathy and/or hepatosplenomegaly by CT scan, at any time during the course of study treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    Major response rate (MRR):
    As assessed by the Independent Review Committee (IRC).

    Duration of Response (DOR):
    As assessed by the investigator or the IRC.

    Rate of CR or VGPR:
    Complete Response (CR): every 24 weeks, at time of suspected complete response (CR), and as clinically indicated.
    Very good partial response (VGPR): as assessed by the investigator.

    Progression Free Survival:
    As assessed by the investigator or the IRC.

    Anti-lymphoma effect:
    At any time during the course of the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    To explore mechanisms of disease resistance in samples from subjects with WM who fail to respond, and from those who manifest disease relapse.
    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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    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
    Australia
    Belgium
    France
    Germany
    Greece
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    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
    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 months6
    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 months6
    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: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 145
    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 state29
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 127
    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)
    After the formal end of the study treatment, patients who were randomised to BGB-3111 will be eligible for continued treatment on a separate extension study. Patients who had been randomised to the ibrutinib arm will not receive therapy on study, but may be transferred to commercially available drug if available or other therapy as per investigator's medical judgement.
    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 Decision2017-01-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-18
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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