Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

Study Overview
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Brief Summary
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The aim of this study is to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.

Official Title
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A Phase 3 Multicentre, Randomized, Prospective, Open-label Trial of Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

Conditions
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Chronic Lymphoid Leukemia

Intervention / Treatment
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* Biological: Ibrutinib
* Biological: Venetoclax
* Biological: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented CLL requiring treatment according to iwCLL criteria. Age at least 18 years. Life expectancy ≥ 6 months. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL: Absolute neutrophil count ≥ 1.0 × 109/L Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to CLL) GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method. a. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome. 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 treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration for study screening (i.e. PCR only required when serology was positive). Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2. Exclusion criteria: Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted). Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation. Patients with a history of PML. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients' safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract). Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician or showing signs of progression after curative treatment. Uncontrolled or active infection. Patients with known infection with human immunodeficiency virus (HIV). Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start). Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients 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 for study screening. Known bleeding disorders Child B / C liver cirrhosis Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening. Vaccination with live vaccines 28 days prior to registration for study screening. Major surgery less than 30 days before start of study treatment. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly). Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment. Legal incapacity. Prisoners or subjects who are institutionalized by regulatory or court order. Persons who are in dependence to the sponsor or an investigator.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I (Ibrutinib)<br>Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first. | Biological: Ibrutinib<br>* Cycles 1 - X: 420 mg daily, d1-28 p.o.<br>* Other names: Imbruvica;|
| Experimental: VG (Obinutuzumab + Venetoclax)<br>12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone | Biological: Venetoclax<br>* Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.<br>* Other names: ABT-199, Venclyxto;Biological: Obinutuzumab<br>* Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v.<br>* Other names: GA101, Gazyvaro;|
| Experimental: VI (Venetoclax + Ibrutinib)<br>15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles | Biological: Ibrutinib<br>* Cycles 1 - X: 420 mg daily, d1-28 p.o.<br>* Other names: Imbruvica;Biological: Venetoclax<br>* Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.<br>* Other names: ABT-199, Venclyxto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed progression-free survival (PFS) | Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first | Up to 80 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM) | Undetectable MRD (uMRD) is defined as <10-4 (=1 CLL-cell per 10,000 leukocytes analyzed).The uMRD rate is defined as the proportion of patients having achieved uMRD. | At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE | 
| MRD levels in PB at different time points | MRD is defined as the number of CLL-cells that can be detected in peripheral blood (PB) or bone marrow (BM). MRD values will be categorized into negative (<10-4) and positive (≥10-4) | Up to 80 month | 
| Overall response rate (ORR) | Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR) as best response. | At final restaging (RE): 18 months after start of treatment | 
| CR/CRi rate | Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the intention-to-treat population (ITT) population) | At final restaging (RE): 18 months after start of treatment | 
| Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI) | Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs | Up to 80 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL