A prospective, open-label, multicenter randomized phase-II trial to evaluate the efficacy and safety of a sequential regimen of obinutuzumab (Gazyvaro) followed by obinutuzumab and venetoclax, followed by either standard venetoclax maintenance or MRD guided venetoclax maintenance in first-line patients with CLL and unfit for FCR-like regimens

INTERVENTION: Trade Name: Gazyvaro Product Name: obinutuzumab Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN Obinutuzumab CAS Number: 949142‐50‐1 Other descriptive name: OBINUTUZUMAB Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 25‐ Product Name: venetoclax 10 mg Pharmaceutical Form: Tablet INN or Proposed INN VENETOCLAX Other descriptive name: venetoclax Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Product Name: venetoclax 50mg Pharmaceutical Form: Tablet INN or Proposed INN : VENETOCLAX Other descriptive name: venetoclax Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: venetoclax 100mg Pharmaceutical Form: Tablet INN or Proposed INN VENETOCLAX Other descriptive name: venetoclax Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ CONDITION: Chronic Lymphocytic Leukemia ; MedDRA version: 19.1 Level: LLT Classification code 10009310 Term: CLL System Organ Class: 100000004864 Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: To separately study the efficacy, defined as MRD negative bone marrow and no progression according to the IWCLL criteria, of the two arms of the study of either venetoclax maintenance or MRD‐guided venetoclax maintenance after sequential regimens of obinutuzumab (pre‐induction) followed by 6 cycles obinutuzumab with venetoclax and 6 cycles of venetoclax (induction) in first‐line patients with CLL and unfit for FCR‐like regimens. Primary end point(s): •MRD negative bone marrow after maximum 24 cycles of (planned) venetoclax and no progression according to IWCLL criteria at any earlier timepoint. Secondary Objective: ‐ To determine efficacy as assessed by additional outcome measures, including overall response, PFS, event free survival (EFS), OS ;; ‐ To determine the impact of the study treatment on quality of life and geriatric scores (including a biological senescence marker of skin biopsy); ‐ Toxicity of venetoclax after pre‐induction, especially tumorlysis and neutropenia; ‐ To identify predictive factors for response and resistance mechanisms via:; ‐ Next‐generation sequencing (NGS) at baseline and at progression; ‐ Flow‐based subset analysis on expression levels of Bcl‐2 proteins at baseline, during therapy and at progression; ‐ Analyses of malignant and non‐malignant immune cells in PB and in LN at baseline and during treatment ; Timepoint(s) of evaluation of this end point: This endpoint will be evaluated when all relevant data of all patients are available and evaluated SECONDARY OUTCOME: Secondary end point(s): • Efficacy as assessed by additional outcome measures, including overall response, PFS, EFS and OS;; • MRD in blood; • Toxicity of venetoclax after pre‐induction, especially tumorlysis and neutropenia; • Quality of life; • Geriatric assessment; • P16 expression in skin biopsy; • Predictive factors for response and resistance mechanisms:; ‐NGS at baseline and at progression; ‐Flow‐based subset analysis on expression levels of Bcl‐2 proteins at baseline, during therapy and at progression; ‐Analyses of malignant and non‐malignant immune cells in PB and in LN at baseline and during treatment ; Timepoint(s) of evaluation of this end point: These endpoints will be evaluated when relevant data for all patients; are available and evaluated INCLUSION CRITERIA: • Diagnosis of symptomatic CLL (according to IWCLL guidelines) • Patients without prior treatment for CLL (Corticoid treatment administered due to necessary immediate intervention is allowed; within the last 10 days before start of study treatment only dose equivalents of maximum 20 mg prednisolone are permitted; • Patients aged = 18 years, not fit for FCR‐like regimens, according to the treating physician; • Able to adhere to the study visit schedule and other protocol requirements; • WHO performance status of = 2 • Laboratory test results within these ranges: ‐ absolute neutrophil count = 1.0 x 109/l and, platelet count and = 50 x 109/l unless due to bone marrow infiltration, ‐ creatinine clearance = 45 ml/min .(using 24‐hour creatinine clearance or modified Cockcroft‐Gault equation ‐ total bilirubin = 1,5 x ULN unless considered due to Gilbert’s syndrome, ‐ transaminases = 3 x ULN; • Negative serum or urin