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    Summary
    EudraCT Number:2020-002622-87
    Sponsor's Protocol Code Number:BeliVeR
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-02
    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 ConcernedGermany - PEI
    A.2EudraCT number2020-002622-87
    A.3Full title of the trial
    A phase II trial of belimumab in combination with
    rituximab/venetoclax in patients with refractory or
    relapsed chronic lymphocytic leukemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II trial of belimumab in combination with
    rituximab/venetoclax in patients with refractory or
    relapsed chronic lymphocytic leukemia
    A.4.1Sponsor's protocol code numberBeliVeR
    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 SponsorUniversity Hospital Tuebingen
    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 supportGlaxoSmithKline
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZentrum für klinische Studien
    B.5.2Functional name of contact pointZKS Tübingen
    B.5.3 Address:
    B.5.3.1Street AddressFrondsbergstrasse 23
    B.5.3.2Town/ cityTübingen
    B.5.3.3Post code72070
    B.5.3.4CountryGermany
    B.5.4Telephone number+4970712985434
    B.5.5Fax number+4970712925080
    B.5.6E-mailzks-pm@med.uni-tuebingen.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 Yes
    D.2.1.1.1Trade name Benlysta 200 mg Injektionslösung im Fertigpen Benlysta 200 mg Injektionslösung in einer Fertigspritze
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline R & D Ltd (GSK)
    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 nameBenlysta 200 mg Injektionslösung im Fertigpen
    D.3.2Product code n.a.
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBELIMUMAB
    D.3.9.1CAS number n.a.
    D.3.9.4EV Substance CodeSUB25607
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    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
    Refractory or relapsed chronic lymphocytic leukemia
    E.1.1.1Medical condition in easily understood language
    Refractory or relapsed chronic lymphocytic leukemia
    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 10009310
    E.1.2Term CLL
    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 assess efficacy (MRD response) of belimumab
    in combination with rituximab/venetoclax in CLL
    compared to treatment with rituximab/venetoclax
    alone.
    E.2.2Secondary objectives of the trial
    • To assess safety of belimumab and rituximab/venetoclax in patients with relapsed or refractory CLL
    • To evaluate overall response rate (ORR)
    • To evaluate progression free survival (PFS)
    • To evaluate overall survival (OS)
    To evaluate duration of response (DOR)
    • To assess further efficacy markers of belimumab in combination with rituximab/venetoclax in CLL compared to control
    • Pharmacokinetics of belimumab in CLL patients
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ≥18 years of age.
    2. Diagnosis of CLL/SLL established according to iwCLL criteria
    3. Refractory or relapsed CLL that warrants treatment (according to modified criteria for initiation of therapy (Hallek et al., 2018)):
    a. Massive (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
    b. Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
    c. Progressive lymphocytosis in the absence of infection, with an increase in blood ALC≥50% over a 2-month period or lymphocyte doubling time of <6 months (as long as initial ALC was ≥30,000/L), or
    d. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or
    e. Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
    i. Unintentional weight loss of ≥10% within the previous 6 months, or
    ii. Significant fatigue (≥Grade 2), or
    iii. Fevers >38.0°C for ≥2 weeks, or
    iv. Night sweats for >1 month.

    4. CLL relapsing after any line of treatment that included radiotherapy, chemotherapy, immunotherapy, or small molecules. Patients who relapse after a previous therapy with venetoclax can be included in the study in case of a late relapse (i.e. >18 months after venetoclax was discontinued.
    5. Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or small molecules) for the treatment of CLL ≥2 weeks before study treatment excluding systemic corticosteroids for symptomatic control.
    6. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before treatment (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, 3, or 4 permitted]).
    7. Eastern Cooperative Oncology Group [ECOG] < 3.
    8. Required baseline laboratory data (within 4 weeks prior to treatment):
    • Serum total bilirubin ≤1.5 x ULN (unless directly attributable to CLL disease or to Gilbert’s Syndrome)
    • ALT/AST ≤2.5 x ULN
    • Renal creatinine clearance >30 ml/min
    • Neutrophile count >1.000/µl (unless directly attributable to the CLL disease)
    9. Negative serological Hepatitis B and C test or negative PCR in case of positive serological test without evidence of an active infection, negative HIV test within 6 weeks prior to treatment.
    10. Written informed consent of the subject

    E.4Principal exclusion criteria
    1. (Suspicion of) transformation of CLL (i.e. Richter’s transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
    2. Early relapse (i.e <18 months) after any line of treatment that included venetoclax.
    3. IgG < 4 g/L under substitution of immunoglobulins
    4. Malignancies other than CLL currently requiring systemic therapies
    5. Evidence of active systemic bacterial (e.g. tuberculosis), fungal, or viral infection (e.g., CMV) at the time of initiation of therapy.
    6. Confirmed progressive multifocal leuk-encephalopathy (PML)
    7. Known history of drug-induced liver injury (DILI), chronic/active hepatitis C (HCV), chronic/active hepatitis B (HBV).
    8. Requirement of therapy with strong CYP3A4 inhibitors/ inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
    9. Active inflammatory bowel disease.
    10. History of prior allogeneic bone marrow or organ transplantation.
    11. Ongoing immunosuppressive therapy. Subjects may use topical, enteric, or inhaled corticosteroids as therapy for comorbidities and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted.
    12. History of primary immunodeficiency
    13. Concurrent participation in another therapeutic clinical trial.
    14. History of serious suicide risk including any suicidal behaviour in the last 6 months
    15. Live vaccination 30 days prior to treatment.
    16. Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure
    17. Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)
    18. Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences
    19. Pregnant or breastfeeding women
    20. Women of childbearing potential, except women who meet the following criteria:
    a. post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum FSH > 40 U/ml)
    b. postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy)
    c. regular and correct use of a contraceptive method with a Pearl Index < 1% per year, which will have to be continued for up to four months after the discontinuation of the study drug
    d. sexual abstinence
    e. Vasectomy of the partner
    21. Male subjects who are able to father a child, except men who meet the following criteria:
    a. willingness to abstain from heterosexual intercourse or use a protocol-recommended method contraception from the screening visit throughout the study treatment period and for four months following the last dose of study drug
    b. refrain from sperm donation from screening visit throughout the study treatment period and for 90 days following the last dose of study drug.
    22. Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance)
    E.5 End points
    E.5.1Primary end point(s)
    Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by
    flow cytometry at EOI
    MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed
    [0.01%], i.e. < 10-4. The MRD negativity rate is defined as the proportion of patients having
    achieved MRD negativity. Patients without any evaluable MRD sample at end of induction treatment
    will be kept and labeled as ‘MRD positive (≥10-4)' in the analysis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    BAseline (14 days before therapy start), visit 1/Day 1 in each cycle (Cycle 1-6), Maintenance Therapy: once in every 4 weeks for 24 months after c1d1 of anti-CD20 therapy; End of treatment (24 months after c1d1 of anti-CD20 therapy) and in the FU Phase (Follow-up every 3 months; +/- 7 days up to 1 year (EOS))
    E.5.2Secondary end point(s)
    Safety (general):
    • Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) through EOT
    • Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) through EOS
    • Incidence of suicidal behavior, as determined by Columbia-Suicide Severity Rating Scale (CSSRS)

    Anti-tumor activity:
    • Number and percentage of overall response rate (ORR) according to iwCLL criteria: PR, CR, and CRi at EOT, as assessed by the investigator at EOI and EOT
    • DOR status as time from best ORR of CR, CRi, or PR until progression
    • Negativity rate of MRD in PB and BM measured by flow cytometry at EOI, every 3 months during maintenance therapy and at EOS
    • TTNT as time from d1 to next other CLL treatment

    Survival:
    • Overall and progression free survival
    • Overall and progression free survival of patients with 17p deletion

    Immunophenotyp:
    • Absolute changes in number and percentage of subjects in lymphocyte subset counts (B, T, NK cells) on day28, d1 of each cycle, EOI and thereafter every 4 weeks until EOT from baseline.

    Pharmacokinetics:
    • Pharmacokinetics of belimumab as assessed as follows:
    o Observed belimumab concentration at c1d1 and EOI

    Quality of life:
    • Overall quality of life scores (EORTC QLQ C-30) until EOS
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the protocol, Trial Schedule
    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 No
    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 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 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) 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 concerned5
    E.8.5The trial involves multiple Member States No
    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 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
    One year after the end of treatment (EOT) a last follow up visit (End of study (EOS)) will be performed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 state120
    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 finishing all study procedures, therapy, and follow-up period, the patient will be followed in terms of routine care and treated if necessary by the primary responsible oncology center. Any attempt should be made by the investigator to follow the patient in particular with regard to any safety issues even after the last assessment.
    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 Decision2021-09-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-27
    P. End of Trial
    P.End of Trial StatusOngoing
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