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Chronic Lymphoid Leukemia in RelapsePhase 2BeliVeRNCT05069051

Belimumab in Patients with Chronic Lymphocytic Leukemia

A Phase 2 study testing Belimumab 200 MG/ML [Benlysta] in people with Chronic Lymphoid Leukemia in Relapse, run by University Hospital Tuebingen at 1 site in Germany.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

This study is a phase II trial of belimumab in combination with rituximab/venetoclax in patients with refractory or relapsed chronic lymphocytic leukemia (CLL). Treatment of CLL has drastically changed in the past years as new therapeutic agents have gained clinical approval. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphoid Leukemia in Relapse
What is being tested?
Belimumab 200 MG/ML [Benlysta]
Could I receive a placebo?
No, everyone receives an active treatment
How many people
120 participants
Where
1 siteGermany
Study dates
19 Jan 2022to 14 Jul 2027
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female ≥18 years of age.
  • Diagnosis of CLL/SLL established according to iwCLL criteria
  • Refractory or relapsed CLL that warrants treatment (according to modified criteria for initiation of therapy (Hallek et al., 2018)):
  • Massive (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
  • Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
  • 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
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  • Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or
  • Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
  • Unintentional weight loss of ≥10% within the previous 6 months, or
  • Significant fatigue (≥Grade 2), or
  • Fevers >38.0°C for ≥2 weeks, or
  • Night sweats for >1 month.
  • 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.
  • 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.
  • 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).
  • Eastern Cooperative Oncology Group [ECOG] < 3.
  • 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 CLL disease)
  • 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.
  • Written informed consent of the subject after clarification

Who cannot join

  • (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
  • IgG < 4 g/L under substitution of immunoglobulins
  • Early relapse (i.e <18 months) after any line of treatment that included venetoclax.
  • Malignancies other than CLL currently requiring systemic therapies
  • Evidence of active systemic bacterial (e.g. tuberculosis), fungal, or viral infection (e.g., CMV) at the time of initiation of therapy
  • Confirmed progressive multifocal leukencephalopathy (PML)
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  • Known history of drug-induced liver injury (DILI), chronic/active hepatitis C (HCV), chronic/active hepatitis B (HBV)
  • Requirement of therapy with strong CYP3A4 inhibitors/ inducers or anticoagulant with phenprocoumon or other vitamin K-antagonists
  • Active inflammatory bowel disease
  • History of prior allogeneic bone marrow or organ transplantation
  • 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
  • History of primary immunodeficiency
  • Concurrent participation in another therapeutic clinical trial
  • History of serious suicide risk including any suicidal behaviour in the last 6 months
  • Live vaccination 30 days prior to treatment
  • Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure
  • Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)
  • 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
  • Pregnant or breastfeeding women
  • Women of childbearing potential, except women who meet the following criteria:
  • post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum FSH > 40 U/ml)
  • postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy)
  • regular and correct use of a contraceptive method with an Pearl Index < 1% per year, which will have to be continued for up to four months after the discontinuation of the study drug
  • sexual abstinence
  • Vasectomy of the partner
  • Male subjects who are able to father a child, except men who meet the following criteria:
  • willingness to abstain from heterosexual intercourse or use a protocolrecommended method contraception from the screening visit throughout the study treatment period and for 90 days following the last dose of study drug
  • refrain from sperm donation from screening visit throughout the study treatment period and for four months following the last dose of study drug
  • Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance)

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • University Hospital Tuebingen, CCU Translational Immunology

    Tübingen, Baden-Wurttemberg, 72076

Other trials in Germany

About this study

Official title: BeliVeR a Phase II Trial of Belimumab in Combination with Rituximab/venetoclax in Patients with Refractory or Relapsed Chronic Lymphocytic Leukemia

This study is a phase II trial of belimumab in combination with rituximab/venetoclax in patients with refractory or relapsed chronic lymphocytic leukemia (CLL). Treatment of CLL has drastically changed in the past years as new therapeutic agents have gained clinical approval. The combination rituximab/venetoclax over a course of two years is approved as second line therapy especially in patients with high risk CLL (del17p), showing high remission rates and achievement of MRD (minimal residual disease) negativity. The next goals in CLL therapy are now to increase the rate of MRD negativity and to achieve an earlier MRD negativity during the course of treatment to allow for a reduction of treatment time and therefore treatment-induced toxicities. In line with other hematologic diseases, progression free survival depends on remission status, especially MRD negativity, after last treatment as MRD positivity after therapy indicates the persistence of treatment resistant CLL cells. One mechanism of therapy resistance has been described as reduced sensitivity to rituximab-induced antibody dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cell production of B-lymphocyte stimulator (BlyS, also called BAFF), which can be bound by belimumab, a human anti-BAFF antibody. Moreover, recombinant human (rh)BAFF can dose dependently reverse cytotoxic effects of venetoclax, which could also be restored by the application of belimumab. This led to the conceptualization of this clinical trial, in which belimumab is applied as a weekly subcutaneous injection in combination with standardrituximab/venetoclax treatment for up to 24 months in relapsed and refractory CLL patients. By removing BAFF from the CLL microenvironment we aim to increase the efficacy of rituximab/venetoclax treatment to achieve higher and earlier MRD negativity rates and allow for an abbreviated treatment.

Read the detailed description

The treatment landscape for relapsed/refractory CLL has faced profound changes and new developments in the past years. Conventional chemoimmunotherapies show only limited efficacy in the relapsed setting and are associated with side effects caused by rather unspecific mode of action of chemotherapy. Therefore, several targeted agents have become available for the treatment of CLL in recent years. However, beside the combination of rituximab and venetoclax all of these substances require continuous treatment bearing the risk of developing therapy resistance and accumulation of side effects. The combination of rituximab and venetoclax shows high response rates in the relapsed setting with MRD negativity rates of 83%, however still requiring a 2-year period of continuous treatment. Future efforts have now to focus on the further and earlier elimination of MRD in all treated patients to allow for a reduced treatment time and therefore lower risks of side effects and development of resistance as well as the achievement of long-lasting remission and potential cure in the future. The available data on the sensitizing effect of belimumab for venetoclax treatment, together with the published results showing a belimumab-induced sensitization of CLL cells to NK cell antitumor immunity as mediated by rituximab, provide a clear rationale for the evaluation of a combinatorial treatment with belimumab to increase sensitivity and response to the established CLL treatment regimen venetoclax/rituximab. Thus, we here propose an open-label, randomized, controlled, multicenter Phase II study analyzing safety and efficacy of belimumab in combination with venetoclax and rituximab in patients with refractory or relapsed CLL.

Justification of combinational treatment The published and preclinical data on the sensitizing effect of belimumab on CLL cells to venetoclax and rituximab provides a clear rationale for combinational treatment of rituximab/venetoclax with belimumab. Although high MRD negativity rates are achieved withrituximab/venetoclax some patients still present with persisting MRD and suffer from early disease relapse. This phase II trial is designed to investigate the efficacy of belimumab in addition to rituximab/venetoclax in relapsed/refractory CLL. The primary endpoint is achievement of MRD negativity at end of induction treatment (EOI). Furthermore, the following secondary objectives will be assessed:

  • Safety of belimumab and rituximab/venetoclax in patients with relapsed or refractory CLL
  • Overall response rate (ORR)
  • Progression free survival (PFS)
  • Overall survival (OS)
  • Duration of response (DOR)
  • Assessment of further efficacy markers of belimumab in combination with rituximab/venetoclax in CLL compared to control
  • Pharmacokinetics of belimumab in CLL patients
Being tested
Belimumab 200 MG/ML [Benlysta], standard of care
Keywords
relapsed CLL, refractory CLL

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Belimumab 200 MG/ML [Benlysta]Drug

    Patients obtain belimumab treatment in combination with rituximab and venetoclax

  • standard of careDrug

    Patients obtain the standard of care: combination rituximab and venetoclax

Study groups in NCT05069051
Study groupRoleWhat they receive
BelimumabExperimentalPatients obtain belimumab in combination with rituximab/venetoclax
Receives: Drug: Belimumab 200 MG/ML [Benlysta]
Standard of CareActive comparatorPatients obtain the combination rituximab/venetoclax
Receives: Drug: standard of care

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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 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.

    Measured: Baseline, Day 1

  2. 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 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.

    Measured: During the intervention: Cycle 1 Day 1, (Cycle length 15 days)

  3. 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 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.

    Measured: During the intervention: Cycle 4 Day 1 (Cycle length 15 days)

  4. 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 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.

    Measured: During 4 weeks after Cycle 6 Day 1 (Cycle length 15 days)

  5. 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 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.

    Measured: End of treatment: 2 years after Cycle 1 at Day 2 (Cycle length 15 days)

  6. 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 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.

    Measured: Follow-Up: every 3 months up to 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Oct 2021
  2. Study start19 Jan 2022
  3. Primary completion15 Jul 2026 (estimated)
  4. Study completion14 Jul 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Open-label, randomized, two-armed controlled, multicenter phase II study analyzing the efficacy and safety of belimumab in combination with venetoclax plus rituximab in patients with refractory or relapsed CLL.
Masking
None (open label)
Enrolment
120 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05069051
Sponsor's protocol ID
BeliVeR, 3.0, 12.11.2021
Acronym
BeliVeR
Status last verified
Nov 2024
First submitted
9 Sep 2021
Last updated
9 Dec 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Belimumab 200 MG/ML [Benlysta] in people with Chronic Lymphoid Leukemia in Relapse, run by University Hospital Tuebingen at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 9 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at EOI (time frame: Baseline, Day 1). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05069051.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2024.

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