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

PRIMARY OBJECTIVES:

I. To compare the progression free survival (PFS) of the time limited administration of the
three-drug combination ibrutinib-obinutuzumab-venetoclax (IOV) to ibrutinib-obinutuzumab (IO)
in untreated chronic lymphocytic leukemia (CLL) patients younger than 70 years of age.

SECONDARY OBJECTIVES:

I. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess
toxicity of treatment based on treatment arm.

QUALITY OF LIFE (QOL) OBJECTIVES:

I. To compare quality of life (QOL) in CLL patients during the first 19 cycles of treatment
among patients on each treatment arm.

II. To compare QOL over the long-term in CLL patients receiving continuous therapy using
ibrutinib to that of CLL patients who completed time limited therapy.

III. Evaluate adherence to therapy for the two arms (one of which requires more intense, but
shorter duration treatment, and one of which requires less intense, but indefinite duration
therapy) and explore how adherence in each arm relates to treatment-free survival (TFS).

EXPLORATORY TOBACCO USE OBJECTIVES:

I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other
forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported
cancer-treatment toxicity (adverse events [both clinical and hematologic]) and dose
modifications.

II. To determine the effects of tobacco on patient-reported physical symptoms and
psychological symptoms.

III. To examine quitting behaviors and behavioral counseling/support and cessation medication
utilization.

IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose
intensity, and therapeutic benefit.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive ibrutinib orally (PO) daily on days 1-28 and obinutuzumab
intravenously (IV) over 4 hours on days 1, 2, 8, and 15 of course 1 and on day 1 of courses
2-6. Patients also receive venetoclax PO once daily (QD) on days 1-28 of courses 3-14.
Treatment repeats every 28 days for up to 19 courses in the absence of disease progression or
unacceptable toxicity.

ARM B: Patients receive ibrutinib PO and obinutuzumab as in arm A. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

All patients, including those who discontinue therapy early, are followed for response until
disease progression, even if non-protocol therapy is initiated. Patients are then followed
every 3 months for first 2 years, every 6 months for years 3-5, and then every 12 months for
years 6-10. All patients must also be followed through completion of all protocol therapy.

Inclusion Criteria:

- Diagnosis of CLL according to the National Cancer Institute (NCI)/International
Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic
lymphoma (SLL) according to the World Health Organization (WHO) criteria. This
includes previous documentation of:

- Biopsy-proven small lymphocytic lymphoma OR

- Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the
following:

- Peripheral blood lymphocyte count of greater than 5 x10^9/L

- Immunophenotype consistent with CLL defined as:

- The predominant 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 restriction
(typically dim immunoglobulin expression)

- Negative fluorescent in situ hybridization (FISH) analysis for
t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate)
or negative immunohistochemical stains for cyclin D1 staining on involved tissue
biopsy (e.g. marrow aspirate or lymph node biopsy).

- No prior chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling
inhibitor, or monoclonal anti-body therapy for treatment of CLL or SLL

- Has met at least one of the following indications for treatment:

- Evidence of progressive marrow failure as manifested by the development of
worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets <
100 x 10^9/L)

- Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

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

- Weight loss >= 10% within the previous 6 months

- Grade 2 or 3 fatigue attributed to CLL

- Fevers > 100.5 degree Fahrenheit (F) for 2 weeks without evidence of
infection

- Clinically significant night sweats without evidence of infection

- Progressive lymphocytosis (not due to the effects of corticosteroids) with an
increase of > 50% over a two-month period or an anticipated doubling time of less
than six months

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

- Life expectancy of >= 12 months

- No deletion of 17p13 on cytogenetic analysis by FISH

- Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault
Formula (obtained =< 14 days prior to registration)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's disease.
For those with a total bilirubin > 1.5 x ULN, a direct bilirubin should be performed
and must be < 1.5 mg/dL for Gilbert's to be diagnosed (obtained =< 14 days prior to
registration)

- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase
[AST])/serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT])
=< 3.0 x the institutional ULN (obtained =< 14 days prior to registration)

- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial
thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN
(obtained =< 14 days prior to registration)

- NOTE: If value is higher due to hepatic involvement by CLL, patient is eligible

- No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
treatment. Patients who have a positive Coombs test but no evidence of hemolysis are
NOT excluded from participation

- No current use of corticosteroids. EXCEPTION: Low doses of steroids (< 10 mg of
prednisone or equivalent dose of other steroid) used for treatment of non-hematologic
medical condition (e.g. chronic adrenal insufficiency) is permitted

- No previous autoimmune complications (e.g. autoimmune hemolytic anemia or immune
thrombocytopenia) that have developed since the initial diagnosis of CLL and have
required treatment with high dose corticosteroids (e.g. equivalent of > 20 mg/day of
prednisone), monoclonal antibody based therapy, or chemotherapy. Prior use of
corticosteroids for reasons other than treatment of autoimmune complications is
allowed

- No other active primary malignancy (other than non-melanomatous skin cancer or
carcinoma in situ of the cervix) requiring treatment or limiting expected survival to
=< 2 years

- NOTE: If there is a history of prior malignancy, the patient must not currently
be receiving other specific treatment (other than hormonal therapy for their
cancer)

- Able to adhere to the study visit schedule and other protocol requirements

- No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery
within 3 days of first dose of study drug

- No radiation therapy =< 4 weeks prior to registration

- Patients who are human immunodeficiency virus positive (HIV+) with undetectable HIV
viral load are eligible provided they meet all other protocol criteria for
participation and are not being treated with protease inhibitors or any non-nucleoside
reverse transcriptase inhibitors (NNRTI) that are CYP3A4 inducers; if being treated
for HIV, patients should be receiving an alternative antiretroviral therapy (ART) that
is not a CYP3A inhibitor

- Patients must not have any of the following conditions:

- Congestive heart failure or New York Heart Association Functional Classification
III or IV congestive heart failure

- History of myocardial infarction, unstable angina, or acute coronary syndrome
within 6 months prior to registration

- Recent infections requiring systemic treatment; need to have completed
anti-biotic therapy > 14 days before the first dose of study drug

- Cerebral vascular accident or intracranial bleed within the last 6 months

- Infection with known chronic, active hepatitis C

- Serologic status reflecting active hepatitis B or C infection. Patients with
hepatitis B or C infection may be eligible if viral loads are undetectable.
Patients may be on suppressive therapy

- Patients are not eligible if they require treatment with a strong cytochrome P450
(CYP) 3A inhibitor

- Patients may not have received the following within 7 days prior to the first dose of
study drug:

- Steroid therapy for anti-neoplastic intent

- Strong and Moderate CYP3A inhibitors

- Strong and Moderate CYP3A inducers

- Patients may not be on any other investigational agents

- Patients may not have received warfarin or another vitamin K antagonist in the
preceding 30 days

- Women must not be pregnant or breast-feeding since this study involves investigational
agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and
newborn are unknown. All females of childbearing potential must have a blood test
within 2 weeks prior to registration to rule out pregnancy. A female of childbearing
potential is any woman, regardless of sexual orientation or whether they have
undergone tubal ligation, who meets the following criteria: 1) has not undergone a
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal
for at least 24 consecutive months (i.e., has had menses at any time in the preceding
24 consecutive months

- Women of childbearing potential and sexually active males must be strongly advised to
use accepted and highly effective method(s) of contraception or to abstain from sexual
intercourse for the duration of their participation in the study and for:

- 18 months after the last dose of obinutuzumab

- 90 days after the last dose of ibrutinib, and

- 30 days after the last dose of venetoclax Male subjects must also agree to
refrain from sperm donation until 90 days after the last dose of protocol
treatment

- Patient must be able to swallow capsules and not have the following conditions:

- Disease significantly affecting gastrointestinal function

- Resection of the stomach or small bowel

- Symptomatic inflammatory bowel disease

- Ulcerative colitis

- Partial or complete bowel obstruction

- Patient must not be on any other systemic immunosuppressant therapy other than
corticosteroids within 28 days of the first dose of study drug

- Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first
dose of study drug

- Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or
hemophilia

- Patient must not have currently active, clinically significant hepatic impairment (>=
moderate hepatic impairment according to the NCI/Child Pugh classification

- Patient must undergo assessment with Timed Up and Go (TUG) test

- Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor
lysis syndrome (TLS) prophylaxis