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    Summary
    EudraCT Number:2018-001366-42
    Sponsor's Protocol Code Number:BGB-3111-305
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-10-17
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-001366-42
    A.3Full title of the trial
    A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared with Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of Zanubrutinib Compared with Ibrutinib in patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
    A.4.1Sponsor's protocol code numberBGB-3111-305
    A.5.4Other Identifiers
    Name: USANNumber:Zanubrutinib
    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.
    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.5.6E-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
    D.3.2Product code BGB-3111
    D.3.4Pharmaceutical form Capsule
    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.3.9.3Other descriptive nameBGB-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.3.9.4EV 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
    Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
    E.1.1.1Medical condition in easily understood language
    Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the efficacy of zanubrutinib versus ibrutinib as measured by overall response
    rate determined by independent central review
    E.2.2Secondary objectives of the trial
     To compare the efficacy of zanubrutinib versus ibrutinib as measured by:
    o Progression-free survival determined by independent central review
    o Progression-free survival determined by investigator assessment
    o Duration of response as determined by independent central review
    o Duration of response as determined by investigator assessment
    o Time to treatment failure
    o Rate of partial response with lymphocytosis or higher determined by independent
    central review
    o Overall survival
    o Patient-reported outcomes
     To compare the safety of zanubrutinib versus ibrutinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient eligible to participate in this study must meet ALL of the following criteria:
    1. Age 18 years or older
    2. Confirmed diagnosis of CLL or SLL that meets the IWCLL criteria
    3. CLL/SLL requiring treatment as defined by at least 1 of the following criteria:
    a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
    b. Massive (≥ 6 cm below left costal margin), progressive, or symptomatic splenomegaly
    c. Massive nodes (≥ 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy
    d. Progressive lymphocytosis with an increase of > 50% over a 2 month period or lymphocyte doubling time of < 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30 x 10 9/L (30,000/µL), lymphocyte doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (eg, infection) should be excluded.
    e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy
    f. Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs:
    i. Unintentional weight loss of ≥ 10% within the previous 6 months
    ii. Significant fatigue (ie, inability to work or perform usual activities)
    iii. Fevers > 100.5ºF or 38ºC for ≥ 2 weeks without other evidence of infection
    iv. Night sweats for > 1 month without evidence of infection
    4. Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current guidelines or of an investigational regimen on a clinical trial
    5. Measurable disease by CT/magnetic resonance imaging (MRI). Measurable disease is defined as ≥ 1 lymph node > 1.5 cm in longest diameter and measurable in 2 perpendicular diameters
    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    7. Life expectancy ≥ 6 months
    8. Adequate bone marrow function as defined by:
    a. Absolute neutrophil count (ANC) ≥ 1000/mm3 (growth factor use is allowed), except for patients with bone marrow involvement in which case ANC must be ≥ 750/mm3
    b. Platelet ≥ 75,000/mm3 (may be post-transfusion), except for patients with bone marrow involvement by CLL in which case the platelet count must be ≥ 50,000/mm3
    9. Patient must have adequate organ function defined as:
    a. Creatinine clearance ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease [MDRD] equation, or as measured by nuclear medicine scan or 24 hour urine collection)
    b. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 2.5 × upper limit of normal unless due to CLL/SLL
    c. Serum total bilirubin < 3.0 × upper limit of normal (unless documented Gilbert’s syndrome)
    10. Female patients of childbearing potential must practice highly effective methods (Section 5.1.2) 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 ibrutinib
    11. Male patients are eligible if vasectomized or if they agree to the use of barrier contraception with other highly effective methods described in Section 5.1.2 during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or ibrutinib
    12. Ability to provide written informed consent and can understand and comply with the requirements of the study.
    E.4Principal exclusion criteria
    Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria:
    1. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation)
    2. 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
    d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes)
    e. QTcF > 480 milliseconds 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 mmHg and diastolic blood pressure > 105 mmHg at screening
    3. 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
    4. 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
    5. History of stroke or intracranial hemorrhage within 180 days before first dose of study drug
    6. Severe or debilitating pulmonary disease
    7. 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
    8. Active fungal, bacterial, and/or viral infection requiring systemic therapy
    9. Known central nervous system involvement by leukemia or lymphoma
    10. 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
    11. Known infection with HIV or serologic status reflecting active viral 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), and if they are willing to undergo 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
    12. Moderate or severe hepatic impairment, ie, Child-Pugh class B or C
    13. Major surgery within 4 weeks of the first dose of study drug
    14. Prior treatment with a BTK inhibitor
    15. Last dose of prior therapy for CLL/SLL ≤ 14 days before randomization, with the following additional exclusion requirements:
    a. Treatment with monoclonal antibody-based therapy within 28 days of first dose of study drug
    b. Treatment with chimeric antigen receptor T-cell therapy within 180 days of first dose of study drug
    c. Treatment with Chinese herbal medicine with anticancer intent within 28 days of first dose of study drug
    d. Chemotherapy or radiation treatment within 21 days of first dose of study drug or hematopoietic stem cell transplantation within 90 days of first dose of study drug
    16. Prior steroid use
    • For prior corticosteroid use of 10mg/day or less, regardless of reason or duration of treatment, must stop steroid no later than day prior to first dose.
    • For prior corticosteroid use of 10mg/day or more, regardless of reason or duration of treatment, must stop steroid 4 weeks prior to date of randomization.
    17. Toxicity from prior anticancer therapy that has not recovered to ≤ Grade 1 (except for alopecia, ANC, and platelet count; for ANC and platelet count, see inclusion criterion 8)
    18. Pregnant or lactating women
    19. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
    20. Ongoing alcohol or drug addiction
    21. Hypersensitivity to zanubrutinib, ibrutinib, or any of the other ingredients in either drug
    22. Patient requires treatment with warfarin or other vitamin K antagonists
    23. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
    24. Concurrent participation in another therapeutic clinical trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is ORR determined by independent central review using the “modified” 2008 IWCLL guidelines with modification for treatment-related lymphocytosis for patients with CLL and per Lugano Classification for non-Hodgkin lymphoma (NHL) for patients with SLL.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analysis will occur approximately 12 months after 400 patients have been randomized.
    E.5.2Secondary end point(s)
    Key Secondary Endpoint:
    - PFS, defined as the time from randomization to the date of first documentation of disease
    progression or death, whichever occurs first, determined by independent central review
    Other Secondary Endpoints:
    - PFS determined by investigator assessment
    - Duration of response, 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,
    determined by independent central review
    - Duration of response by investigator assessment
    - Time to treatment failure, defined as time from randomization to discontinuation of study
    drug due to any reason
    - Rate of PR-L or higher, defined as the proportion of patients who achieve a CR/CRi + PR + nodular PR + PR-L determined by independent central review
    - Overall survival, defined as the time from randomization to the date of death due to any cause
    - PROs measured by the EQ-5D-5L and EORTC QLQ-C30 questionnaires
    - Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs
    E.5.2.1Timepoint(s) of evaluation of this end point
    The final analysis will occur approximately 12 months after 400 patients have been randomized.

    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 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 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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA83
    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
    China
    Czech Republic
    France
    Germany
    Italy
    Netherlands
    New Zealand
    Poland
    Spain
    Sweden
    Turkey
    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 years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 320
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 204
    F.4.2.2In the whole clinical trial 400
    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
    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 Decision2018-11-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-30
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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