A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib + Venetoclax 15 cycles
- Conditions
- Chronic Lymphocytic Leukemia in Relapse
- Sponsor
- Stichting Hemato-Oncologie voor Volwassenen Nederland
- Enrollment
- 230
- Locations
- 49
- Primary Endpoint
- Number of patients with progression free survival 27 months after starting treatment
- Status
- Active, not recruiting
- Last Updated
- 3 years ago
Overview
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.
Investigators
Eligibility Criteria
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)
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.
Arms & Interventions
Ibrutinib until progression/relapse
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse
Intervention: Ibrutinib + Venetoclax 15 cycles
Ibrutinib until progression/relapse
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse
Intervention: Ibrutinib until progression/relapse
Arm A
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)
Intervention: Ibrutinib + Venetoclax 15 cycles
Arm A
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)
Intervention: Ibrutinib until progression/relapse
Arm B
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm B: Observation until event. Patients randomized to Arm B will get reinitiation of therapy during the observation period in case of: * progression according to IWCLL criteria or * MRD≥10-3 (PB) and at least one month later MRD ≥10-2 (PB). Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles
Intervention: Ibrutinib + Venetoclax 15 cycles
Outcomes
Primary Outcomes
Number of patients with progression free survival 27 months after starting treatment
Time Frame: 27 months after last patient in trial
arm B of the study
Secondary Outcomes
- Number of patients with progression free survival(7 years after last patient in)
- Number of patients initiating new CLL treatment(7 years after last patient in)
- Number of patients with treatment failure after reinitiating treatment(7 years after last patient in)
- Number of patients with MRD negativity 27 months after starting treatment(27 months after last patient in trial)
- Number of patients reinitiating treatment(7 years after last patient in)
- 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)
- 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)
- Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires)(51 months after last patient in trial)
- Number of patients alive(7 years after last patient in)
- 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)