Belimumab in Patients With Chronic Lymphocytic Leukemia (BeliVeR)

This is an interventional treatment trial for Chronic Lymphoid Leukemia in Relapse focused on measuring relapsed CLL, refractory CLL Read More

Inclusion Criteria:

• 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)):

  1. Massive (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
  2. Massive (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
  3. 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
  4. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or

  5. 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

Exclusion Criteria:

• (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
• 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)