Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Older Patients With Untreated Chronic Lymphocytic Leukemia

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) between control treatment and experimental
treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus
ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

SECONDARY OBJECTIVES:

I. To compare bone marrow (BM) minimal residual disease (MRD)- complete response (CR) rates
and depth of response at cycle 15 day 1 between patients treated with IO versus IVO.

II. To compare overall survival (OS) between the control and experimental treatment
strategies: IO with IM versus IVO regardless of IM or observation.

III. To compare the 5-year PFS and overall survival (OS) for the control and experimental
treatment strategies: IO with IM versus IVO regardless of IM or observation.

IV. To describe the toxicity profile for each of the treatment strategies and by each
treatment course.

CORRELATIVES OBJECTIVES:

I. To compare MRD status between blood and bone marrow at the end of induction
treatment/cycle 15 day 1 to determine whether blood MRD can be used as a surrogate to bone
marrow MRD with these treatment regimens.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Patients also
receive obinutuzumab intravenously (IV) on days 1, 2, 8, and 15 of cycle 1, and on day 1 of
cycles 2-6. Treatment repeats every 28 days for up to 14 cycles in the absence of disease
progression or unacceptable toxicity. Beginning cycle 15, patients receive ibrutinib PO QD
every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive ibrutinib PO QD on days 1-28. Patients also receive obinutuzumab IV
on days 1, 2, 8, and 15 of cycle 1, and on day 1 of cycles 2-6. Beginning cycle 3, patients
also receive venetoclax PO QD on days 1-28. Treatment repeats every 28 days for 14 cycles in
the absence of disease progression or unacceptable toxicity. Beginning cycle 15, patients who
do not achieve a BM MRD negative CR, receive ibrutinib PO QD every 28 days in the absence of
disease progression or unacceptable toxicity. Patients who achieve a BM MRD negative CR
undergo observation every 3 cycles for 6 years, then every 6 cycles thereafter.

After completion of study treatment, followed every 6 months until 10 years from
registration.

Inclusion Criteria:

- PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

- Patients must have been diagnosed with chronic lymphocytic leukemia (CLL) and have >
5000 B-cells per uL of peripheral blood at any point during the course of their
disease

- This blood submission is mandatory prior to registration/randomization to perform
fluorescence in situ hybridization (FISH) centrally that will be used for
stratification. It should be obtained as soon after pre-registration as possible

- REGISTRATION ELIGIBILITY CRITERIA (STEP 1)

- Patients must be diagnosed with CLL in accordance with 2018 International Workshop on
Chronic Lymphocytic Leukemia (IWCLL) criteria that includes all of the following:

- >= 5 x10^9 B lymphocytes (5000/uL) in the peripheral blood measured by flow
cytometry at any point in the course of the disease

- On local morphologic review, the leukemic cells must be small mature lymphocytes,
and prolymphocytes must not exceed 55% of the blood lymphocytes

- CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell
population, which express the B cell surface markers of CD19 and CD20, as well as
the T-cell antigen CD5. Patients with bright surface immunoglobulin expression or
lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by
interphase cytogenetics

- Patients must be intermediate or high-risk Rai stage CLL

- Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus
enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly

- High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without
enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or
thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to
autoimmune hemolytic anemia or thrombocytopenia

- Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines which
includes at least one of the following criteria:

- Evidence of marrow failure as manifested by the development or worsening of
anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
thrombocytopenia)

- Massive (>= 6 cm below the costal margin), progressive or symptomatic
splenomegaly

- Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
therapy

- Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine)

- Constitutional symptoms, which include any of the following:

- Unintentional weight loss of 10% or more within 6 months

- Significant fatigue

- Fevers > 100.5 degrees Fahrenheit (F) for 2 weeks or more without evidence
of infection

- Night sweats >= 1 month without evidence of infection

- Patients must not have had prior therapy for CLL (except palliative steroids or
treatment of autoimmune complications of CLL with rituximab or steroids)

- Treatment with rituximab and/or high dose corticosteroids for autoimmune complications
of CLL must be complete at least 4 weeks prior to enrollment. Palliative steroids must
be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at
the time of registration

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) >= 1,000/mm3 except if due to bone marrow involvement

- Platelet count (untransfused) >= 30,000/mm3

- Calculated (Calc.) creatinine clearance >= 40 mL/min (by Cockcroft-Gault)

- Bilirubin =< 1.5 x upper limit of normal (ULN) except if due to liver involvement,
hemolysis, or Gilbert's disease

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN) except if due to liver involvement

- Patients must not have any history of Richter's transformation or prolymphocytic
leukemia (prolymphocytes in blood > 55%)

- If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be
undetectable on suppressive therapy if indicated

- Please note: Intravenous immunoglobulin therapy (IVIG) can cause a false positive
hepatitis B serology. If patients receiving routine IVIG have core antibody or surface
antigen positivity without evidence of active viremia (negative hepatitis B
deoxyribonucleic acid [DNA]) they may still participate in the study, must have
hepatitis serologies and hepatitis B DNA monitored periodically by the treating
physician

- If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV
viral load

- Patients with class III or class IV heart failure by New York Heart Association, those
with unstable angina, and those with uncontrolled arrhythmia are not eligible

- Patients who have had a myocardial infarction, intracranial bleed, or stroke within
the past 6 months are not eligible

- Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- Patients must not be receiving active systemic anticoagulation with heparin or
warfarin. Patients on warfarin must discontinue the drug for at least 10 days prior to
registration on the study

- Chronic concomitant treatment with strong inhibitors of CYP3A4/5 is not allowed on
this study. Patients on strong CYP3A inhibitors must discontinue the drug for 14 days
prior to registration on the study

- Chronic concomitant treatment with strong CYP3A4/5 inducers is not allowed. Patients
must discontinue the drug 14 days prior to registration on the study

- Patients must not require more than 20 mg prednisone or equivalent corticosteroid
daily

- Patients must not have uncontrolled active systemic infection requiring intravenous
antibiotics

- Patients must be able to swallow capsules and not have the following conditions:
disease significantly affecting gastrointestinal absorption, resection of the stomach
or small bowel, partial or complete bowel obstruction

- Patients must not have a known allergy to mannitol

- Patients must not have prior significant hypersensitivity to rituximab (not including
infusion reactions)

- Patients may not have had major surgery within 10 days prior to registration, or minor
surgery within 7 days prior to registration. Examples of minor surgery include dental
surgery, insertion of a venous access device, skin biopsy, or aspiration for a joint.
The decision about whether a surgery is major or minor can be made at the discretion
of the treating physician

- Patients must be able to receive either a xanthine oxidase inhibitor or rasburicase
for prophylaxis/treatment of tumor lysis syndrome (TLS)

- RE-REGISTRATION ELIGIBILITY CRITERIA (STEP 2)

- Completion of treatment through cycle 14 day 28, and remain on ibrutinib therapy

- Receipt of central BM MRD results

- Response assessment completed with CR determination