Trial of Ibrutinib Plus Venetoclax Plus Obinutuzumab in Patients With CLL

Inclusion Criteria: 1. Have documented CLL according to iwCLL criteria, measurable disease (lymphocytosis \> 5x109 and/or palpable and measurable lymph nodes by physical exam and/or organomegaly assessed by physical exam) 2. Subjects must have untreated CLL, i.e. no prior chemotherapy, antibody therapy or non-chemotherapeutic agent (BTK, PI3K, BCL2 inhibitor or similar). Local irradiation or short term (up to 1 month) corticosteroid treatment for autoimmune phenomena are allowed 3. Subjects must have TP53 deletion (17p-) and/or mutation (in bone marrow or peripheral blood), with pre-existing local test results confirmed by central laboratory in Ulm 4. CLL requiring treatment ("active disease") according to the iwCLL criteria 5. ECOG ≤ 2 6. Creatinine clearance ≥ 50 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection 7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST, and ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome 8. No cardiovascular disability of New York Heart Association (NYHA) Class \> 2. Class 2 is defined as comfortability at rest but moderate physical activity causes dyspnoea, angina pain or fatigue 9. Adequate bone marrow function (unless directly attributable to CLL, BM examination required): * ANC ≥ 1000/µl or * ANC \< 1000/µl, if attributable to the underlying CLL (growth factor support may be administered after screening) * Platelets \> 30.000/µl (unless directly attributable to the underlying CLL) * Hemoglobin ≥ 8g/dl (unless directly attributable to the underlying CLL) 10. Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative) negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration. \[Patients who are HBsAg negative/anti-HBc positive with undetectable serum HBV DNA should be monitored closely (every month) for HBV DNA by a real-time PCR quantification assay with a lower limit of detection of the order of 10 WHO IU/mL until at least 24 months after the last treatment cycle with obinutuzumab. If the HBV DNA assay becomes positive, patients should pre-emptively be treated with a nucleoside analogue (i.e. lamivudine) for at 24 months after the last cycle of therapy with obinutuzumab or be referred to a gastroenterologist for management.\] 11. Age at least 18 years 12. Life expectancy ≥ 6 months 13. Must be able to adhere to the study visit schedule and other protocol requirements 14. Able and willing to provide written informed consent and to comply with the study protocol procedures Exclusion Criteria: 1. Transformation of CLL (i.e. Richter's transformation, prolymphocyctic leukemia) 2. One or more individual organ / system impairment score of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system 3. Known central nervous system (CNS) involvement 4. Patients with a history of PML 5. Active malignancies other than CLL within the past 2 years prior to study entry, with the exception: * Adequately treated in situ carcinoma of the cervix uteri * Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and in remission at time of screening 6. Use of agents which would interfere with the study drug within 28 days prior to registration 7. Uncontrolled infection requiring systemic treatment 8. History of severe infusion-related reaction to humanized or murine monoclonal antibodies, and/ or known sensitivity or allergy to murine products or allergy to xanthin oxidase and rasburicase or glucose-6-phosphate dehydrogenase deficiency 9. Requires treatment with the following drugs: * Within 7 days prior to the first dose of study drug: No steroid therapy higher than 20 mg Prednisolone for anti-neoplastic intent; No CYP3A inhibitors (e.g. fluconazole, ketoconazole, clarithromycin, warfarin or phenprocoumon); No potent CYP3A inducers (e.g., rifampin, phenytoin or carbamazepine); * Within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade); Star fruit. 10. History of stroke or intracranial hemorrhage within 6 months prior to registration 11. Pregnant women and nursing mothers 12. Fertile men or women of childbearing potential unless: 1. surgically sterile or ≥ 2 years after the onset of menopause 2. willing to use two highly effective contraceptive methods (Pearl Index \<1) during study treatment and for 18 months after end of study treatment. 13. Vaccination with a live vaccine a minimum of 28 days prior to registration 14. Legal incapacity 15. Prisoners or subjects who are institutionalized by regulatory or court order 16. Persons who are in dependence to the sponsor or an investigator