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    Summary
    EudraCT Number:2018-002492-17
    Sponsor's Protocol Code Number:CLL-RT1
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-12-19
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2018-002492-17
    A.3Full title of the trial
    A prospective, open-label, multicentre Phase-II-Trial to evaluate the efficacy and safety of zanubrutinib (BGB-3111), a BTK Inhibitor, plus tislelizumab (BGB-A317), a PD-1 Inhibitor, for treatment of patients with Richter Transformation.
    Eine prospektive, unverblindete, multizentrische Phase-II-Studie zur Evaluation der Effektivität und Sicherheit von Zanubrutinib (BGB-3111), einem BTK-Inhibitor in Verbindung mit Tislelizumab, einem PD-1 Inhibitor, zur Behandlung von Patienten mit einer Richter-Transformation.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of a Treatment with tislelizumab and zanubrutinib in patients with a Richter Transformation.
    Bewertung einer Behandlung mit Tislelizumab und Zanubrutinib bei Patienten mit einer Richter-Transformation.
    A.3.2Name or abbreviated title of the trial where available
    CLL-RT1
    A.4.1Sponsor's protocol code numberCLL-RT1
    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 SponsorUniversität zu Köln
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBeiGene Ltd.
    B.4.2CountryCayman Islands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGerman CLL Study Group
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressGleueler Str. 176-178
    B.5.3.2Town/ cityKöln
    B.5.3.3Post code50935
    B.5.3.4CountryGermany
    B.5.4Telephone number0049022147888220
    B.5.5Fax number0049022147886886
    B.5.6E-mailcllstudie@uk-koeln.de
    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.2.1.1.1Trade name Tislelizumab
    D.2.1.1.2Name of the Marketing Authorisation holderBeiGene Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameTislelizumab
    D.3.2Product code BGB-A317
    D.3.4Pharmaceutical form Concentrate and solvent for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtislelizumab
    D.3.9.1CAS number 1858168-59-8
    D.3.9.3Other descriptive nameBGB-A317
    D.3.9.4EV Substance CodeSUB189550
    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 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 Yes
    D.3.11.13.1Other medicinal product typeTislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.1.1.1Trade name Zanubrutinib
    D.2.1.1.2Name of the Marketing Authorisation holderBeiGene Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.9.3Other 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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product 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
    Patients excluded are:
    -Primary progressive patients, i.e. patients who did not respond to their first-line treatment (=> Exclusion criteria 1)
    -Patients with 2 or more prior lines of therapy (=> Exclusion criteria 2)

    Two groups of patients with RT are eligible (=> Inclusion criteria 3):
    - Patients without previous treatment
    - Patients with 1 prior line of therapy only if they responded to therapy
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated Richter Transformation or patients who responded to up to one prior line of RT therapy
    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 LLT
    E.1.2Classification code 10008975
    E.1.2Term Chronic lymphocytic leukaemia variants
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of a combinational therapy with tislelizumab and zanubrutinib in CLL pa-tients with Richter transformation to DLBCL.
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate the safety of combinational therapy with tislelizumab and zanubrutinib in CLL patients with Richter transformation to DLBCL.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Confirmed diagnosis of CLL according to iwCLL criteria (Hallek et al, 2018) [13]
    2. Confirmed histopathological diagnosis of RT
    3. Creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection
    4. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless di-rectly attributable to the patient’s CLL/RT or to Gilbert’s Syndrome, in which case a max. total bilirubin ≤ 4 x and AST/ALT ≤ 5 x the institutional ULN value are required.
    5. Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every two months until 2 months after last dose of zanubrutinib), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
    6. Age at least 18 years
    7. ECOG performance status 0-2, ECOG 3 is only permitted if related to CLL or RT (e.g. due to anaemia or severe constitutional symptoms)
    8. Life expectancy ≥ 6 months
    9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
    E.4Principal exclusion criteria
    1. Patients who did not respond to previous line of RT therapy (i.e. primary progressive patients)
    2. Patients with more than one prior line of RT therapy
    3. Allogenic stem cell transplantation within the last 100 days or signs of active GVHD after prior allogeneic stem cell transplantation within any time
    4. Patients with confirmed PML
    5. Uncontrolled autoimmune condition
    6. Malignancies other than CLL currently requiring systemic therapies
    7. Active infection currently requiring systemic treatment
    8. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, exclud-ing the eyes/ears/nose/throat/larynx organ system, or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion could comprise the patients safety or interfere with the absorption or metabolism of the study drugs
    9. Requirement of therapy with strong CYP3A4 inhibitors/ inducers
    10. Requirement of therapy with phenprocoumon or other vit-amin K antagonists.
    11. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times half-life [t1/2] of the compound, whichever is longer) prior to registration
    12. Known hypersensitivity to tislelizumab, zanubrutinib or any of the excipients
    13. Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing potential within 7 days before start of treatment)
    14. Fertile men or women of childbearing potential unless:
    - surgically sterile or ≥ 2 years after the onset of meno-pause, or
    - willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months af-ter the end of study treatment.
    15. Vaccination with a live vaccine <28 days prior to randomi-zation
    16. Legal incapacity
    17. Prisoners or subjects who are institutionalized by regula-tory or court order
    E.5 End points
    E.5.1Primary end point(s)
    Overall response rate (ORR) after induction therapy (i.e. 6 cycles) according to the refined Lugano Classification (Cheson et al, 2016).
    - Complete response (CR)
    - Partial response (PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    After induction therapy (i.e. 6 cycles)
    E.5.2Secondary end point(s)
    • ORR after induction therapy (i.e. 6 cycles) according to IWCLL criteria (Hallek et al, 2018)
    • ORR after consolidation therapy (i.e. 12 cycles)
    • Duration of response
    • Progression-free survival (PFS)
    • Overall survival (OS)
    • Time to next treatment (TTNT)
    • Proportion of patients receiving SCT for consolidation
    • Exploratory endpoints: Evaluation of relationship between various baseline markers, including PD-1/PD-L1 expression and mutational load, and clinical outcome parameters
    • Safety parameters: type, frequency, severity of adverse events (AEs), and their relationship to study treatment
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR after induction therapie (i.e. 6 cycles)
    ORR after consolidation therapy (i.e. 12 cycles)
    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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days15
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 48
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-28
    P. End of Trial
    P.End of Trial StatusOngoing
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