Front-line VenObi Combination Followed by Ven or VenZan Combination in Patients With Residual Disease: a MRD Tailored Treatment for Young Patients With High-risk CLL

Inclusion Criteria:

1. Patients older than 18 years and 65 years or less.
2. Diagnosis of CLL meeting the iwCLL 2018 criteria.
3. Total CIRS <6, creatinine clearance >30 ml/min [Cockcroft-Gault]) and ECOG performancestatus of 0-1.
4. No prior treatment.
5. Patients with unmutated IGHV, and, or TP53 mutation assessed by an ERIC certifiedlaboratory, and, or deletion 17p assessed by FISH analysis.
6. Active disease meeting at least 1 of the iwCLL 2018 criteria for treatmentrequirement.
7. Adequate hematologic parameters unless due to disease under study:

• Absolute neutrophil count (ANC) ≥1.0 x 109/L unless neutropenia is clearly due todisease under study (per investigator discretion)
• Platelet count ≥ 75,000/mm3 - OR - Platelet count ≥ 20,000/mm3 ifthrombocytopenia is clearly due to disease under study (per investigatordiscretion)
• Hemoglobin ≥9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion)

8. Adequate renal and hepatic function, per laboratory reference range at screening asfollows:

• AST/SGOT, ALT/SGPT ≤2.0 x ULN
• Total bilirubin ≤1.5 x ULN unless considered secondary to Gilbert's syndrome, inwhich case ≤3 x ULN

9. QT-interval corrected according to Fridericia"s formula (QTcF) ≤450 milliseconds (ms).
10. For females of childbearing potential, a negative serum pregnancy test within 7 daysof study treatment.
11. For female patients of childbearing potential, agreement to use highly effectiveform(s) of contraception (i.e., one that results in a low failure rate [<1% per year]when used consistently and correctly) or remain abstinent (refrain from heterosexualintercourse) during the treatment period and to continue its use for 90 days after thelast dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18months after the last dose of obinutuzumab (whichever date is later). For men with afemale partner of childbearing potential or a pregnant female partner: agreement toremain abstinent (refrain from heterosexual intercourse) or use a condom during thetreatment period and to continue its use for 90 days after the last dose ofzanubrutinib, or venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later).
12. A signed informed consent document indicating that they understand the purpose of andthe procedures required for the study, including biomarkers, and are willing toparticipate in the study.
13. Ability and willingness to comply with the requirements of the study protocol.

Exclusion Criteria:

1. Any significant concurrent, uncontrolled medical condition or organ system dysfunctionand laboratory abnormality or psychiatric disease, which, in the investigator'sopinion, could compromise the subject's safety or put the study outcomes at undue riskor prevent the subject from signing the informed consent form.
2. Known active histological transformation from CLL to an aggressive lymphoma (i.e.,Richter's transformation or pro-lymphocytic leukemia);
3. known central nervous system involvement.
4. Active malignancy or systemic therapy for another malignancy within 3 years Except:

• Malignancies surgically treated with curative intent and with no known active diseasepresent for ≥ 3 years before randomization

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Surgically/adequately treated low grade, early stage localized prostate cancer withoutevidence of disease

5. Co-morbidities:

• Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
• Any uncontrolled illness that in the opinion of the investigator would precludeadministration of study therapy
• History of stroke or intracranial hemorrhage within 180 days before first dose ofstudy drug.
• History of severe bleeding disorder or history of spontaneous bleeding requiring bloodtransfusion or other medical intervention due to thrombocytopenia or inherited oracquired bleeding disorders due to deficiency or functional abnormality of anycoagulation proteins.
• History of significant cardiovascular disease, defined as:

1. Congestive heart failure greater than New York Heart Association (NYHA) class IIaccording to the NYHA functional classification.
2. Unstable angina or myocardial infarction with 6 months of enrollment.
3. Serious cardiac arrhythmia or clinically significant ECG abnormality: correctedQT wave (QTcF) > 480 msec based on the Fridericia's formula or other ECGabnormalities including second-degree atrioventricular block type II,third-degree atrioventricular block. Participants who have a pacemaker will beallowed on study despite ECG abnormalities or the inability to calculate the QTc.

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episodeof infection requiring treatment with IV antibiotics or hospitalization (relating tothe completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1
• History of tuberculosis within the last five years or recent exposure to tuberculosisequal to or less than 6 months.
• History of progressive multifocal leukoencephalopathy (PML)
• History of HIV infection or active hepatitis B (chronic or acute) or hepatitis Cinfection 1. Patients with occult or prior HBV infection (defined as positive totalhepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA isundetectable. These patients must be willing to take appropriate anti-viralprophylaxis as indicated and undergo monthly DNA testing.

2. Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA.

• Inadequate renal function: CrCl < 30 mL/min.
• Clinically significant history of liver disease, including viral or other hepatitis,current alcohol abuse, or cirrhosis.
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonalantibodies or known sensitivity or allergy to murine products
• Known intolerance or hypersensitivity to any of the components of the therapeuticregimen
• Receipt of live-virus vaccines within 28 days prior to the initiation of studytreatment or need for live-virus vaccines at any time during study treatment.
• Prior major surgical procedure within 4 weeks of study, or anticipation of need for amajor surgical procedure during the course of the study
• Known condition or other clinical situation that would affect oral absorption.
• Psychiatric illness/social situations that would interfere with study compliance.
• Inability to swallow a large number of tablets.

6. Concomitant medications and drug interactions:

• Patients who are on treatment with the following agents within 7 days prior totreatment: Strong CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin Strong CYP3Ainducers such as rifampin, carbamazepine and strong inhibitors or inducers of CYP2C8,CYP2C9 and CYP2C19. The same applied for moderate inhibitors or inducers of CYP3A Requireswarfarin, marcumar, or phenprocoumon (due to potential drug-drug interactions that maypotentially increase the exposure of warfarin or phenprocoumon)

• Prior anti-CD20 monoclonal antibody therapy for non-malignant indication 7. Females who are currently pregnant or breastfeeding. 8. Participation in a separate investigational therapeutic study unless authorized by theinvestigator.