Chronic Lymphocytic Leukemia in Relapse, Chronic Lymphocytic Leukemia in Remission
Conditions
Brief summary
The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.
Interventions
DRUGIbrutinib + Venetoclax 15 cycles
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 \| Cycle 3: 420 mg ibrutinib, day 1-28 \| 20 mg venetoclax, day 1-7 \| 50 mg venetoclax, day 8-14 \| 100 mg venetoclax, day 15-21 \| 200 mg venetoclax, day 22-28 \| Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28
DRUGIbrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
DRUGPossible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles
Cycle 1: 420 mg ibrutinib \| 20 mg venetoclax, day 1-7 \| 50 mg venetoclax, day 8-14 \| 100 mg venetoclax, day 15-21 \| 200 mg venetoclax, day 22-28 \| cycles 2-12: 420 mg ibrutinib, day 1-28 + 400 mg venetoclax, day 1-28
Sponsors
Nordic CLL Study Group
Stichting Hemato-Oncologie voor Volwassenen Nederland
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. Patients not achieving MRD negativity after cycle 12 (PB) AND/OR cycle 15 (PB+BM) continue on ibrutinib maintenance (non-randomized group). Patients achieving MRD negativity after cycle 12 (PB) AND cycle 15 (PB+BM) are randomized 1:2 between ibrutinib maintenance (arm A) and stopping treatment (observation, arm B).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy. * Age at least 18 years. * Adequate bone marrow function defined as: * Absolute neutrophil count (ANC) \>0.75 x 109/L * Platelet count \>30,000 /μL 30 x 109/L. * Hemoglobin \>8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy * Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection. * Adequate liver function as indicated * Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN) * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin) * Prothrombin time (PT)/International normal ratio (INR) \<1.5 x ULN and PTT (activated partial thromboplastin time \[aPTT\]) \<1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder). * Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration. * WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL. * Negative pregnancy test at study entry (for women of childbearing potential). * Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug. * Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. * Written informed consent.
Exclusion criteria
* Any prior therapy with ibrutinib and/or venetoclax. * Transformation of CLL (Richter's transformation). * Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML). * Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment. * Known allergy to xanthine oxidase inhibitors and/or rasburicase. * Known bleeding disorders (e.g., von Willebrand's disease or hemophilia). * Uncontrolled or active infection. * Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib. * History of stroke or intracranial hemorrhage within 6 months prior to registration. * Major surgery within 28 days prior to registration. * Use of investigational agents which might interfere with the study drug within 28 days prior to registration. * Vaccination with live vaccines within 28 days prior to registration * Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids. * Pregnant women and nursing mothers. * Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with progression free survival 27 months after starting treatment | 27 months after last patient in trial | arm B of the study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with progression free survival | 7 years after last patient in | all arms of the study |
| Number of patients reinitiating treatment | 7 years after last patient in | arm B of the study |
| Number of patients with treatment failure after reinitiating treatment | 7 years after last patient in | arm B of the study |
| Number of patients initiating new CLL treatment | 7 years after last patient in | all arms of the study |
| Number of patients with MRD negativity 27 months after starting treatment | 27 months after last patient in trial | all arms of the study |
| Number of patients alive | 7 years after last patient in | all arms of the study |
| Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group | 7 years after last patient in | all arms of the study |
| Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis) | 7 years after last patient in | all arms of the study |
| Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires) | 51 months after last patient in trial | all arms of the study |
| Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment | 15 months after last patient in trial | all arms of the study |
Countries
Belgium, Denmark, Finland, Netherlands, Norway, Sweden
Outcome results
None listed