Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. To compare the bone marrow minimal residual disease (MRD)-negative complete response (CR)
rate of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage asymptomatic
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients who are high and
very high risk by CLL-International Prognostic Index (IPI). (Arms A and B) II. To evaluate
time to first therapy (TFT) in early stage asymptomatic CLL/SLL patients with low and
intermediate-risk by CLL-IPI. (Arm C)

SECONDARY OBJECTIVES:

I. To compare the safety of acalabrutinib alone and acalabrutinib/obinutuzumab in early stage
asymptomatic CLL/SLL patients who are high and very high risk by CLL-IPI.

II. To compare the overall response rate (ORR), progression-free survival (PFS), time to next
therapy (TNT) and overall survival (OS) of acalabrutinib alone and acalabrutinib/obinutuzumab
in early stage asymptomatic CLL/SLL patients who are at high and very high risk by CLL-IPI.

III. To determine the progression-free survival (PFS) and overall survival (OS) in early
stage asymptomatic CLL/SLL patients with low and intermediate risk by CLL-IPI.

EXPLORATORY OBJECTIVES:

I. To evaluate the quality of life using Functional Assessment of Cancer Therapy-General
(FACT-G) quality of life (QOL) survey.

CORRELATIVE RESEARCH:

I. To compare the peripheral blood immune profile using 8-color flow cytometry, to assess
changes in T-cells, natural killer (NK)-cells, and NK-T cells at baseline and during active
treatment among patients receiving either acalabrutinib alone or acalabrutinib and
obinutuzumab.

II. To determine changes in the peripheral blood immune profile using 8-color flow cytometry
to assess changes in T-cells, NK-cells, and NK-T cells at baseline and during event
monitoring in patients with low and intermediate risk by CLL-IPI.

III. Signal pathway studies-BTK, ERK, PLC gamma and S6 protein levels and phosphorylation
status will be assessed by Western blot methodology using specific antibodies to pull down
specific proteins from cell lysates.

IV. To confirm if in vitro cell killing is via apoptosis we will also assess PARP and caspase
3 cleavage.

V. Apoptotic protein studies-MCL-1, XIAP levels will be determined by Western blot
methodology using specific antibodies to pull down these specific proteins from cell lysates.

VI. Bone marrow aspirates will be studied for hematopoietic function in two ways: estimation
of colony forming capacity by purified hematopoietic stem cells (HSCs) and evaluation of the
levels of HSCs and their differentiated progeny (i.e. MPP, CMP, CLP).

VII. Paired bone marrow and blood samples will be evaluated for the levels of innate effector
cells.

VIII. Perform targeted sequencing of 59 genes mainly grouped in 8 biological pathways:
NOTCH1, B-cell signaling, deoxyribonucleic acid (DNA) damage response, chromatin modifiers,
ribonucleic acid (RNA) metabolism, NF-kappaB pathway, cell cycle and apoptosis.

OUTLINE: Participants with high or very high risk CLL-IPI are randomized to Arm A or Arm B.
Participants with intermediate or low risk are assigned to Arm C.

ARM A: Participants receive acalabrutinib orally (PO) twice daily (BID) on days 1-28.
Treatment repeats every 28 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84. Treatment
repeats every 84 days for 6 courses in the absence of disease progression or unacceptable
toxicity. Participants may continue treatment with acalabrutinib If MRD negative CR/CR with
incomplete marrow recovery (CRi) is not achieved after 12 courses.

ARM B: Participants receive acalabrutinib orally (PO) twice daily (BID) on days 1-28 and
obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of course 1 and days 1 of subsequent
courses. Treatment repeats every 28 days for 6 courses in the absence of disease progression
or unacceptable toxicity. Participants then receive acalabrutinib PO BID on days 1-84.
Treatment repeats every 84 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Participants may continue treatment with acalabrutinib If MRD negative
CR/CRi is not achieved after 12 courses.

ARM C: Participants will be observed every 6 months for up to 2 years.

After completion of study treatment, participants are followed up every 6 months for up to 5
years.

Inclusion Criteria:

- Diagnosis of:

- Biopsy-proven small lymphocytic lymphoma (SLL) , or

- Diagnosis of chronic lymphocytic leukemia (CLL) with a clonal B-cell population
in the peripheral blood with immunophenotyping consistent with CLL as follows:

- The population of lymphocytes share both B-cell antigens (CD19, CD20
[typically dim expression], or CD23) as well as CD5 in the absence of other
pan-T-cell markers (CD3, CD2, etc.)

- Clonality as evidenced by kappa or lambda light chain expression (typically
dim immunoglobulin expression) or other genetic method (e.g. IGHV analysis)

- Before diagnosing CLL or SLL, mantle cell lymphoma must be excluded by
demonstrating a negative fluorescence in situ hybridization (FISH) analysis
for t(11;14)(IgH/CCND1)

- Patients must be previously untreated (see Note)

- Note: Prior chemotherapy or monoclonal antibody based therapy for treatment of
CLL or SLL will be considered prior therapy. Nutraceutical treatments with no
established benefit in CLL (such as epigallocatechin gallate or EGCG, found in
green tea or other herbal treatments or supplemental vitamins) will not be
considered "prior treatment". Prior corticosteroid therapy for an indication
other than CLL/SLL will not be considered "prior treatment".

- All patients will undergo testing for prognostic factors according to the CLL-IPI
(testing obtained ≤120 days prior to registration), as shown in Appendix V.

Note: Patients with CLL-IPI risk category of High Risk or Very High Risk (total score of
4-10) will be randomized to Arms A or B Note: Patients with CLL-IPI risk category of low
risk or intermediate risk (total score of 0-3) will be registered to Arm C.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

- Provide written informed consent

- Willing to provide blood and saliva samples for correlative research purposes

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: Absolute neutrophil count (ANC) ≥1500/mm^3

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: Platelet count ≥ 100,000/mm^3

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: Hemoglobin ≥ 11.0 g/dL

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: Aspartate aminotransferase (aspartate transaminase [AST]) ≤ 3 x
upper limit of normal (ULN)

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤ 30 days prior
to randomization: Creatinine ≤ 1.5 X ULN

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (or total
bilirubin ≤ 3.0 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with
well-documented Gilbert's syndrome)

- For high risk and very high risk CLL-IPI (Arms A and B) only; obtained ≤30 days prior
to randomization: prothrombin time (PT), international normalized ratio (INR), and
partial thromboplastin time (PTT) ≤ 1.5 X ULN OR if patient is receiving anticoagulant
therapy and PT or PTT is within therapeutic range of intended use of coagulants

- Negative serum pregnancy test done ≤ 7 days prior to registration, for persons of
childbearing potential only

- Will provide bone marrow aspirate sample for correlative research purposes

Exclusion Criteria:

- Date of CLL/SLL diagnosis ≥ 24 months prior to registration

- Prior exposure to ibrutinib or to a BCR inhibitor (eg Btk or PI3 kinase or Syk
inhibitors) or a BCL-2 inhibitor (eg venetoclax)

- Known central nervous system (CNS) lymphoma or leukemia

- Patients with any of the following indications for chemotherapy:

- Evidence of progressive marrow failure as manifested by the development of or
worsening anemia (≤ 11 g/dL) and/or thrombocytopenia (≤ 100 x 10^9/L) not due to
autoimmune disease

- Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly

- One or more of the following disease-related symptoms:

- Weight loss ≥ 10% within the previous 6 months

- Extreme fatigue attributed to CLL

- Fevers ≥ 100.4 degree Fahrenheit (F) for 2 weeks without evidence of
infection

- Drenching night sweats without evidence of infection

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Patients known to be human immunodeficiency virus (HIV) positive and currently
receiving antiretroviral therapy; NOTE: Patients known to be HIV positive, but without
clinical evidence of an immunocompromised state, are eligible for this trial

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Other active malignancy ≤2 years prior to registration; EXCEPTIONS: Non-melanotic skin
cancer, carcinoma-in-situ of the cervix, or early stage prostate cancer

- History of myocardial infarction ≤6 months prior to registration, or congestive heart
failure requiring use of ongoing maintenance therapy for life-threatening ventricular
arrhythmias

- For high risk and very high risk CLL-IPI (Arms A and B) only:

- Any of the following:

- Pregnant persons

- Nursing persons

- Persons of childbearing potential who are unwilling to employ highly
effective contraception

- Serologic status reflecting active hepatitis B or C infection

- NOTE: Subjects with hepatitis B core antibody positive who are surface
antigen negative or who are hepatitis C antibody positive will need to have
a negative polymerase chain reaction (PCR) result before randomization;
those who are hepatitis B surface antigen positive or hepatitis B PCR
positive and those who are hepatitis C PCR positive will be excluded

- History of stroke or intracranial hemorrhage within 6 months before randomization

- History of bleeding diathesis (e.g. hemophilia, von Willebrand disease)

- Requires or receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g. phenprocoumon) within 7 days of first dose of study drug and
while on study

- Requires treatment with a strong CYP3A inducer

- Requires treatment with proton-pump inhibitors (e.g. omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole)

- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months
before screening

- History of confirmed progressive multifocal leukoencephalopathy (PML)

- Received a vaccination with a live vaccine ≤ 28 days prior to randomization