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About
Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. By combining ibrutinib with venetoclax, cells can be mobilized from tissues into the bloodstream by ibrutinib and killed in the blood by venetoclax. Consistently, the venetoclax-ibrutinib combination can achieve undetectable minimal residual disease (MRD-neg) in a sizable proportion of patients. Gentle debulking obtained with a lead-in phase of ibrutinib monotherapy may allow starting venetoclax when the disease has been reshaped in a size that fits for low-risk of tumor lysis syndrome (TLS), a rare adverse event (AE) of venetoclax. MRD-guided treatment duration may allow patients achieving a negative status to gain drug-free intervals and less medicalization, and may avoid all the potential, and not yet completely known implications of continuous therapy on long-term safety, drug interactions, quality of life, compliance to treatment, and economic sustainability.
Full description
Background:
The standard of care for treatment of patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) has substantially changed. Current standard for patients with a relapse later than 3 years from first-line therapy is a repetition with the first-line regimen used. This poses the risk of significant immunosuppression and infectious complications as well as a shorter event-free survival as expected for first-line treatment. Current standard for patients with refractory disease, early relapse or emerging TP53 defective clones, is a targeted treatment with ibrutinib, idelalisib + rituximab or venetoclax as continuous therapy until progression or toxicity.
Rationale:
Venetoclax and ibrutinib are both oral drugs whose tolerability when used in combination is not inferior to single agents. Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. Ibrutinib is more active in lymph nodes rather than blood where a small lymphocytosis might persist despite continuous treatment. Conversely, venetoclax appears to be more active in blood and bone marrow (BM) rather than lymph nodes. By combining ibrutinib with venetoclax, cells can be mobilized from tissues into the bloodstream by ibrutinib and killed in the blood by venetoclax. Consistently, the venetoclax-ibrutinib combination can achieve undetectable minimal residual disease (MRD-neg) in a sizable proportion of patients. Gentle debulking obtained with a lead-in phase of ibrutinib monotherapy may allow starting venetoclax when the disease has been reshaped in a size that fits for low-risk of tumor lysis syndrome (TLS), a rare adverse event (AE) of venetoclax. MRD-guided treatment duration may allow patients achieving a negative status to gain drug-free intervals and less medicalization, and may avoid all the potential, and not yet completely known implications of continuous therapy on long-term safety, drug interactions, quality of life, compliance to treatment, and economic sustainability.
The primary objective of the trial is to assess efficacy after 30 cycles of trial treatment.
Enrollment
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Ages
Volunteers
Inclusion criteria
Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures
Cytologically and immunophenotypically confirmed relapsed/refractory CLL (irrespective of the 17p deletion and/or TP53 mutation status and the duration of remission from last prior therapy)
Patients in need of systemic treatment as defined by international workshop on chronic lymphocytic leukemia (iwCLL) criteria (at least one of the following indications must be fulfilled):
Age at least 18 years
WHO performance status 0-2
Hematological function:
Hepatic function:
Renal function: Creatinine clearance > 30 mL/min (calculated according to institutional standards or using Cockcroft-Gault formula
Adequate coagulation parameters per local laboratory reference range as follows: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN
Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and during the 30 days thereafter. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential
Men agree not to father a child during trial treatment and during 3 months thereafter
Patient is able and willing to swallow trial drugs as whole tablet/capsule
Patient is willing to participate in translational research
Exclusion criteria
Any potential patient who meets any of the following criteria has to be excluded from entering the trial.
Primary purpose
Allocation
Interventional model
Masking
30 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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