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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Lymphocytic Leukemia in Relapse, Chronic Lymphocytic Leukemia in Remission

Intervention / Treatment
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* Drug: Ibrutinib + Venetoclax 15 cycles
* Drug: Ibrutinib until progression/relapse
* Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib until progression/relapse<br>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 | Drug: Ibrutinib + Venetoclax 15 cycles<br>* 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<br>Drug: Ibrutinib until progression/relapse<br>* 420mg ibrutinib daily until progression/relapse<br>|
| Experimental: Arm A<br>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) | Drug: Ibrutinib + Venetoclax 15 cycles<br>* 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<br>Drug: Ibrutinib until progression/relapse<br>* 420mg ibrutinib daily until progression/relapse<br>|
| Experimental: Arm B<br>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 | Drug: Ibrutinib + Venetoclax 15 cycles<br>* 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<br>Drug: Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with progression free survival 27 months after starting treatment | arm B of the study | 27 months after last patient in trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with MRD negativity 27 months after starting treatment | all arms of the study | 27 months after last patient in trial | 
| Number of patients with progression free survival | all arms of the study | 7 years after last patient in | 
| Number of patients reinitiating treatment | arm B of the study | 7 years after last patient in | 
| Number of patients with treatment failure after reinitiating treatment | arm B of the study | 7 years after last patient in | 
| Number of patients initiating new CLL treatment | all arms of the study | 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 | all arms of the study | 15 months after last patient in trial | 
| Number of patients alive | all arms of the study | 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 | all arms of the study | 7 years after last patient in | 
| Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis) | all arms of the study | 7 years after last patient in | 
| Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires) | all arms of the study | 51 months after last patient in trial |