MAJIC: A Phase III Prospective, Multicenter, Randomized, Open- Label Trial of Acalabrutinib plus Venetoclax versus Venetoclax plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A study of acalabrutinib plus venetoclax (AV) versus venetoclax plus obinutuzumab (VO) in
previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Inclusion Criteria:

1. Participant must be ≥ 18 years at the time of signing the consent form.

2. Documented TN CLL/SLL requiring treatment according to iwCLL guidelines 2018 (Hallek
et al 2018).

3. Adequate BM function independent of growth factor or platelet transfusion support
within 2 weeks of screening initiation as follows:

1. Absolute neutrophil count ≥ 1.0 × 10 9 /L; absolute neutrophil count ≥ 500
cells/μL (≥ 0.50 × 109/L) with documented bone marrow (BM) involvement of
chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL).

2. Platelet counts ≥ 30 × 10 9 /L; platelet count ≥ 10 × 10 9 /L in participants
with documented BM involvement of CLL/SLL.

4. Estimated CrCL of ≥ 30 mL/min calculated by Cockcroft-Gault (using actual body
weight) or serum creatinine < 2 × ULN,

Males:

CrCL (mL/min) = Weight (kg) × (140 - Age)/72 × serum creatinine (mg/dL)

Females:

CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85/72 × serum creatinine (mg/dL)

5. Meet the following laboratory parameters (Upper limit of normal (ULN) is based on
institutional standards):

1. Serum AST and ALT ≤ 3 × ULN (Higher thresholds may be allowed if hepatic
dysfunction is attributable to CLL/SLL and after discussion with the Sponsor
Hematology Safety Knowledge Group).

2. Total bilirubin ≤ 1.5 × ULN, unless directly attributable to Gilbert's
syndrome.

6. An ECOG (Eastern Cooperative Oncology Group) performance status performance status
of 0 to 2 with no deterioration over the previous 2 weeks prior to baseline or day
of first dosing.

7. Ability to understand the purpose and risks of the study and provide signed and
dated informed consent and authorization to use protected health information (in
accordance with national and local patient privacy regulations).

8. Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules and tablets without difficulty.

Exclusion Criteria:

1. As judged by the investigator, any evidence of past or current diseases that, in the
investigator's opinion, makes it undesirable for the participant to participate in
the study or that would jeopardize their safety or compliance with the protocol or
would put the study at risk.

2. Clinically significant cardiovascular disease, such as symptomatic arrhythmias,
congestive heart failure, or myocardial infarction, within 6 months of screening or
any Class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification. Note: Participants with controlled, asymptomatic atrial
fibrillation can enroll in the study.

3. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand
disease).

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.

5. History of significant cerebrovascular disease/event, including stroke or
intracranial hemorrhage, within 6 months before the first dose of study
intervention.

6. Child-Pugh B/C liver cirrhosis.

7. History of prior or current malignancy (including but not limited to known central
nervous system involvement such as by CLL/SLL, leptomeningeal disease, or spinal
cord compression, known prolymphocytic leukemia or history of, or currently
suspected, Richter's syndrome) that could affect compliance with the protocol or
interpretation of results. Possible examples where compliance or data interpretation
may not be affected could include the following, per physician discretion.

1. Curatively treated basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)
of the skin or carcinoma in situ of the cervix or carcinoma in situ of the
prostate at any time prior to study.

2. Other cancers that have been curatively treated from which the participant is
disease-free for ≥ 3 years without further treatment.

8. An individual organ system dysfunction limiting the ability to receive the study
intervention or any other life-threatening illness, medical condition, or organ
system dysfunction that, in the investigator's opinion, could compromise the
participants' safety or interfere with the absorption, distribution, metabolism, or
excretion of the study interventions (eg, refractory nausea and vomiting, chronic
gastrointestinal disease, inability to swallow the formulated product, previous
significant bowel resection, or impaired resorption in the gastrointestinal tract).

9. Known history of infection with HIV or any active significant infection (eg,
bacterial, viral, or fungal; including participants with positive cytomegalovirus
(CMV) DNA PCR). CMV testing at screening must include serologic testing for CMV
immunoglobulin G (CMV IgG), CMV immunoglobulin M (CMV IgM), and CMV DNA PCR testing.
Participants must have a result for CMV DNA PCR that is negative at screening to be
eligible for the study.

10. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).

11. Serologic status reflecting active hepatitis B or C infection:

1. Hepatitis serology will include HBsAg, anti-HBs, anti-HBc and anti-HCV. Any
participant who is both anti-HBc positive and HBsAg negative will need to have
a negative HBV DNA PCR result before randomization and must be willing to
undergo this PCR testing during the study. Any participant who is either HBsAg
positive or hepatitis B DNA PCR positive will be excluded.

2. Participants who are hepatitis C antibody positive or inconclusive will need to
have a negative HCV RNA PCR result before randomization. Those who are
hepatitis C PCR positive will be excluded.

12. Any prior CLL/SLL-specific therapies, except prior rituximab if used for autoimmune
cytopenias and not as anti-CLL/SLL treatment.

13. Corticosteroid use > 20 mg within 1 week before the first dose of study
intervention, except as indicated for other medical conditions, such as autoimmune
cytopenias, inhaled steroid for asthma, topical steroid use, or as premedication for
administration of study intervention or contrast. Participants requiring steroids at
daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are
administered steroids for leukemia control or white blood cell count lowering, are
excluded. Of note, participants may receive corticosteroids as doses > 20 mg as per
institutional standards for obinutuzumab premedication prior to C1D1.

14. Prior radio- or toxin-conjugated antibody therapy.

15. Prior allogeneic stem cell or autologous transplant.

16. Known history of hypersensitivity or anaphylaxis to study intervention(s), including
active product or excipient components.

17. Requires treatment with a strong cytochrome CYP3A4 inhibitor/inducer. The use of
strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the
first dose of study drug is prohibited.

18. Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (other anticoagulants allowed).

19. Requires treatment with proton pump inhibitors (PPIs) (eg, omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Participants
receiving PPIs who switch to H2-receptor antagonists or antacids are eligible for
enrollment to this study. This criterion applies only to participants receiving
acalabrutinib capsules. This PPI exclusion does not apply if the participant is
receiving acalabrutinib tablets.

20. Vaccination with live vaccines 28 days prior to registration for study screening.

21. Major surgical procedure within 28 days of first dose of study intervention. Note:
If a participant had major surgery, they must have recovered adequately from any
toxicity and/or complications from the intervention before the first dose of study
intervention.

22. Concurrent participation in another therapeutic clinical trial. Use of
investigational agents that interfere with the study intervention(s) within 28 days
or 5 half-lives (whichever is longer) prior to registration for study screening.

23. Prothrombin time/INR or activated partial thromboplastin time, in the absence of
lupus anticoagulant or attributed to anticoagulant (eg, direct oral anticoagulant),
> 2 × ULN.

24. Currently pregnant (confirmed with positive pregnancy test) or breast feeding.

25. Women of childbearing Potential (WOCBP) unless the following criteria are met: A
negative pregnancy test at least 30 days before start of study intervention,
followed by immediate highly effective contraception; further pregnancy testing will
be performed monthly.

26. Fertile men or WOCBP unless the following criteria are met: Willing to use 2 methods
of reliable contraception, including one highly effective contraceptive method
(Pearl Index < 1) and one additional effective (barrier) method during study
intervention and for 2 days after last acalabrutinib dose (for WOCBP), 30 days after
last venetoclax dose (fertile men and WOCBP), and 6 months after last obinutuzumab
dose for fertile men and 18 months after last obinutuzumab dose for WOCBP.