The Combination of Venetoclax and Obinutuzumab in People With Chronic Lymphocytic Leukemia (CLL)

Inclusion Criteria:

• Signed informed consent form.

• Ability and willingness to comply with the requirements of the study protocol.

• Age ≥18 years.

• Have documented previously untreated chronic lymphocytic leukemia according to iwCLL / WHO criteria.

• Require treatment of CLL per iwCLL guidelines.

• CIRS score ≤ 6 (patient's CLL diagnosis is not included in CIRS score).

• Eastern Cooperative Oncology Group Performance Status of 0 or 1.

• Adequate hematologic function (unless caused by underlying disease, as establishedby extensive bone marrow involvement or as a result of hypersplenism secondary tothe involvement of the spleen by CLL per the investigator) defined as follows:

• Hemoglobin ≥ 8 g/dL without transfusion support, unless anemia is due to marrowinvolvement of CLL.

• Absolute neutrophil count ≥ 1.0 x 10^9/L.

• Platelet count ≥ 30 x 10^9/L; in cases of thrombocytopenia clearly due tomarrow involvement of CLL (per the discretion of the investigator), plateletcount should be ≥ 10 x 10^9/L if there is bone marrow involvement.

• Adequate renal function, as indicated by modified Cockcroft-Gault equation (eCCR;with the use of ideal body mass [IBM] instead of mass) of > 50mL/min

• Adequate liver function, as indicated by:

• AST or ALT ≤ 2.5 x ULN.

• Total bilirubin ≤ 1.5 x ULN (or ≤ 5 x ULN for patients with documented Gilbertsyndrome).

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use a contraceptive method with a failure rate of < 1%per year during the treatment period and for at least 30 days after the last dose ofvenetoclax or 18 months after the last dose of obinutuzumab, whichever is longer.

• Women must refrain from donating eggs during this same period.

• A woman is considered to be of childbearing potential if she is postmenarcheal,has not reached a postmenopausal state (> 12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus).

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices.

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm, as definedbelow:

• With female partners of childbearing potential, men must remain abstinent oruse a condom plus an additional contraceptive method that together result in afailure rate of < 1% per year during the treatment period and for at least 90days after the last dose of venetoclax or 18 months after the last dose ofobinutuzumab, whichever is longer. Men must refrain from donating sperm duringthis same period.

• With pregnant female partners, men must remain abstinent or use a condom forthe duration of the pregnancy to avoid exposing the embryo.

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.

Exclusion Criteria:

• Prior CLL-directed therapy. Patients may have received a brief (≤7 days) course ofsystemic steroids prior to initiation of study therapy for control oflymphoma-related symptoms.

• Transformation of CLL to aggressive NHL (Richter's transformation or prolymphocyticleukemia).

• Known hypersensitivity to any of the study drugs.

• History of prior malignancy, except for conditions as listed below if patients haverecovered from the acute side effects incurred as a result of previous therapy:

• Malignancies treated with curative intent and with no known active diseasewithin 2 years

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease (no time constraint).

• Adequately treated cervical carcinoma in situ without evidence of disease (notime constraint).

• Surgically/adequately treated low grade, early stage, localized prostate cancerwithout evidence of disease (no time constraint).

• 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.

• Requires the use of warfarin (because of potential drug-drug interactions that maypotentially increase the exposure of warfarin).

• Received the following agents within 7 days prior to the first dose of venetoclax:

• Strong and moderate CYP3A inhibitors.

• Strong and moderate CYP3A inducers.

• Consumed grapefruit, grapefruit products, Seville oranges (including marmaladecontaining Seville oranges), or star fruit within 3 days prior to the firstdose of venetoclax.

• Clinically significant history of liver disease, including active viral or otherhepatitis, current alcohol abuse, or cirrhosis

• Presence of positive test results for hepatitis B virus (HBV), hepatitis B surfaceantigen (HBsAg), or hepatitis C (HCV) antibody

• Patients who are positive for HCV antibody must be negative for HCV bypolymerase chain reaction (PCR) to be eligible for study participation

• Patients with occult or prior HBV infection (defined as positive totalhepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBVDNA is undetectable. These patients must be willing to undergo monthly DNAtesting and should consider antiviral prophylaxis as per institutionalstandards.

• Known infection with HIV or human T-cell leukemia virus 1 (HTLV-1)

• 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

• Pregnant or lactating, or intending to become pregnant during the study

°Women of childbearing potential must have a negative serum pregnancy test resultwithin 21 days prior to initiation of study drug per institutional standards.

• Recent major surgery (within 4 weeks prior to the start of Cycle 1, Day 1) otherthan for diagnosis.

• Inability to swallow a large number of tablets.

• Malabsorption syndrome or other condition that precludes enteral route ofadministration. This is subject to investigator discretion.

• Known allergy to both xanthine oxidase inhibitors and rasburicase.