Zanubrutinib With Obinutuzumab in Untreated Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Inclusion Criteria:

1. Adult patients with previously untreated CLL defined following IWCLL criteria (Hallek, 2018).

2. Must understand and voluntarily sign an informed consent form.

3. Age ≥ 18 years at the time of signing the informed consent form and must be able toadhere to the study visit schedule and other protocol requirements.

4. Must have a documented diagnosis of CLL or SLL [IWCLL guidelines for diagnosis andtreatment of CLL (Hallek, 2018)] meeting at least one of the following criteria:

• Evidence of progressive marrow failure as manifested by the development of, orworsening of, anemia and/or thrombocytopenia.

• Massive (i.e. ≥6 cm below the left costal margin) or progressive or symptomaticsplenomegaly.

• Massive nodes (i.e. ≥10 cm in longest diameter) or progressive or symptomaticlymphadenopathy.

• Progressive lymphocytosis with an increase of ≥50% over a 2-month period, orlymphocyte doubling time (LDT) of less than 6 months.

• A minimum of any one of the following disease-related symptoms: unintentionalweight loss ≥ 10% within the previous 6 months, significant fatigue (i.e., ECOGPS 2 or worse; cannot work or unable to perform usual activities), fevers ofgreater than 38.0°C for 2 or more weeks without other evidence of infection, ornight sweats for more than 1 month without evidence of infection.

• Autoimmune complications including anemia or thrombocytopenia poorly responsiveto corticosteroids.

• Symptomatic or functional extranodal involvement (eg, skin, kidney, lung,spine).

5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.

6. Female patients of childbearing potential must practice highly effective methods ofcontraception initiated prior to first dose of study drug, for the duration of thestudy, and for ≥ 90 days after the last dose of zanubrutinib and 18 months afterlast dose of obinutuzumab. Male patients are eligible if vasectomized or if they agree to the use of barriercontraception with other applicable highly effective methods described below duringthe study treatment period and for ≥ 90 days after the last dose of zanubrutinib and 18 months after last dose of obinutuzumab. A woman is considered of childbearing potential, ie, fertile, following menarche anduntil becoming postmenopausal unless permanently sterile. Permanent sterilizationmethods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.Contraception methods include the following:

• Combined (estrogen- and progestogen- containing) hormonal contraceptionassociated with the inhibition of ovulation - Oral, intravaginal, ortransdermal.

• Progestogen-only hormonal contraception associated with the inhibition ofovulation - Oral, injectable, implantable.

• An intrauterine device.

• Intrauterine hormone-releasing system.

• Bilateral tubal occlusion.

• Vasectomized partner (provided that the vasectomized partner is the sole sexualpartner of the woman of childbearing potential study participant and that thevasectomized partner has received medical assessment of surgical success).

• Sexual abstinence (defined as refraining from heterosexual intercourse duringthe entire period of risk associated with the study treatment, starting the dayprior to first dose of study drug, for the duration of the study, and for ≥ 90days after the last dose of zanubrutinib or ibrutinib. Total sexual abstinenceshould only be used as a contraceptive method if it is in line with thepatients' usual and preferred lifestyle. Periodic abstinence (eg, calendar,ovulation, symptothermal, post-ovulation methods), declaration of abstinencefor the duration of exposure to investigational medicinal product, andwithdrawal are not acceptable methods of contraception. Of note, barrier contraception (including male and female condoms with or withoutspermicide) is not considered a highly effective method of contraception, and, ifused, this method must be used in combination with another acceptable method listedabove. If patient is using hormonal contraceptives such as birth control pills or devices,a barrier method of contraception (eg, condoms) must also be used. A postmenopausal state is defined as no menses for 12 months without an alternativemedical cause. A high follicle-stimulating hormone level in the postmenopausal rangemay be used to confirm a postmenopausal state in women not using hormonalcontraception or hormonal replacement therapy. However, in the absence of 12 monthsof amenorrhea, a single follicle-stimulating hormone measurement is insufficient.

7. Female subjects of childbearing potential must have a negative pregnancy test atscreening. Females of child bearing potential are defined as sexually mature womenwithout prior hysterectomy or who have had any evidence of menses in the past 12months. However, women who have been amenorrheic for 12 or more months are stillconsidered to be of childbearing potential if the amenorrhea is possibly due toother causes, including prior chemotherapy, anti-estrogens, or ovarian suppression.

Exclusion Criteria:

1. Prior treatment for CLL.

2. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis CVirus (HCV) infection. Subjects who are hepatitis B core antibody (anti-HBc)positive and who are surface antigen negative could be eligible if they have anundetectable HBV DNA (negative polymerase chain reaction (PCR) <20 IU). Those whoare hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will beexcluded. Subjects who are hepatitis C antibody positive will need to have anegative PCR result. Those who are hepatitis C PCR positive will be excluded. Per published guidelines (NCCN 2012) or institutional guidelines, patients should beclosely monitored for hepatitis B reactivation. Obtaining repeated hepatitis B PCRevery 3 months during treatment and for the 12 months after last dose of study drugaccording to usual clinical practice in order to monitor for reactivation ofhepatitis B is recommended.

3. Estimated Glomerular Filtration Rate (Cockcroft-Gault Appendix C) ≤30 mL/min/1.73m2.

4. Absolute neutrophil count (ANC) < 1.0 X 109/L.

5. Platelet count < 75 X 109/L, except for patients with bone marrow involvement by CLLin which case the platelet count must be ≥ 30 X 109/L.

6. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >2.5 x upper limit of normal (ULN).

7. Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert's syndrome.

8. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.

9. Active bleeding, history of bleeding diathesis (eg, haemophilia or von Willebranddisease).

10. Unable to swallow capsules, or has disease significantly affecting gastrointestinalfunction that would limit absorption of oral medication.

11. Currently active, clinically significant cardiovascular disease or a history ofmyocardial infarction within 3 months prior to enrollment. Exception: Subjects withcontrolled, asymptomatic atrial fibrillation during screening can enrol on study.

12. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists (eg, phenprocoumon) within 7 days of first dose of study drug.

13. Systemic infection that has not resolved prior to initiating study treatment inspite of adequate anti-infective therapy.

14. Pregnant or lactating females.

15. Participation in any clinical study or having taken any investigational therapywithin 28 days prior to initiating study therapy.

16. Central nervous system (CNS) involvement as documented by spinal fluid cytology orimaging.

17. Prior history of malignancies, other than CLL, unless the patient has been free ofthe disease for ≥ 3 years. Exceptions include the following:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

18. Presence of autoimmune haemolytic anaemia or autoimmune thrombocytopenia.

19. Major surgery within the last 28 days prior to registration.

20. History of stroke or intracranial haemorrhage within 6 months prior to enrollment.

21. Requires treatment with strong CYP3A4/5 Inhibitors.

22. Known history of drug-specific hypersensitivity or anaphylaxis to study drug (including active product or excipient components).

23. Any life-threatening illness, medical condition, or organ system dysfunction which,in the Investigator's opinion, could compromise the subject's safety, interfere withthe absorption or metabolism of zanubrutinib, or put the study outcomes at unduerisk.