Belimumab in Patients with Chronic Lymphocytic Leukemia

NCT05069051 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: BeliVeR, 3.0, 12.11.2021
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Chronic Lymphoid Leukemia in Relapse

Keywords

relapsed CLL; refractory CLL

Outcome Measures

Primary Outcomes (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.

  Baseline, Day 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

  Follow-Up: every 3 months up to 1 year

Study Arms (2)

Belimumab

EXPERIMENTAL

Patients obtain belimumab in combination with rituximab/venetoclax

Drug: Belimumab 200 MG/ML [Benlysta]

Standard of Care

ACTIVE COMPARATOR

Patients obtain the combination rituximab/venetoclax

Drug: standard of care

Interventions

Belimumab 200 MG/ML [Benlysta] DRUG

Patients obtain belimumab treatment in combination with rituximab and venetoclax

Belimumab

standard of care DRUG

Patients obtain the standard of care: combination rituximab and venetoclax

Standard of Care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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).

You may not qualify if:

• (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)
• 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

Sponsors & Collaborators

• University Hospital Tuebingen: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

University Hospital Tuebingen, CCU Translational Immunology

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

MeSH Terms

Interventions

belimumab; Standard of Care

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Juliane Walz, Prof.Dr.

  University Hospital Tuebingen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 9, 2021
• First Posted: October 6, 2021
• Study Start: January 19, 2022
• Primary Completion (Estimated): July 15, 2026
• Study Completion (Estimated): July 14, 2027
• Last Updated: December 9, 2024

Record last verified: 2024-11

Locations

DE (1)