Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia
Ibrutinib and Obinutuzumab With or Without Venetoclax in Treating Patients With Chronic Lymphocytic Leukemia
This phase III trial studies how well ibrutinib and obinutuzumab with or without venetoclax
 work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of
 cancer cells by blocking some of the enzymes needed for cell growth. Obinutuzumab is a
 monoclonal antibody that may interfere with the ability of cancer cells to grow and spread.
 Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer
 cell survival. Giving ibrutinib, obinutuzumab, and venetoclax may work better than giving
 ibrutinib and obinutuzumab in treating patients with chronic lymphocytic leukemia.
PRIMARY OBJECTIVE:

 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. III. Compare minimal residual disease (MRD)
 status as assessed by flow cytometry at baseline and then sequentially during treatment of
 the two treatment arms.

 IV. Collect baseline and response evaluation (after cycle 19) bone marrow and paired blood
 specimens for evaluation of MRD.

 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 progression-free survival (PFS).

 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 cycle 1 and on day 1 of cycles
 2-6. Patients also receive venetoclax PO once daily (QD) on days 1-28 of cycles 3-14.
 Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or
 unacceptable toxicity.

 ARM B: Patients receive ibrutinib PO and obinutuzumab as in arm A. Cycles 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; inhaled steroids) 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 to Step 1

 -  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

 -  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 undergo assessment with Timed Up and Go (TUG) test and comorbidity index

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

 Exclusion Criteria:

 -  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

 -  Positive serology for hepatitis B defined as a positive test for hepatitis B
 surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core
 antibody (HBcAb) positive (regardless of hepatitis B surface antibody [HBsAb]
 status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed and, if
 positive the subject will be ineligible; if the hepatitis (Hep) B DNA test is
 negative (i.e. viral load undetectable) then the individual is eligible; if a
 patient who is HBsAg negative, HBcAb positive, and Hep B DNA negative is
 enrolled, they should be considered for either prophylactic anti-viral therapy (J
 Clin Oncol. 2013 Aug 1;31(22):2765-72) or careful monitoring for Hep B
 reactivation (J Clin Oncol. 2014 Nov 20;32(33):3736-43)

 -  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 Step 1 to rule out pregnancy; a female of
 childbearing potential is defined as any woman, regardless of sexual orientation or
 whether they have undergone tubal ligation, who meets the following criteria: 1) has
 achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
 oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer
 therapy does not rule out childbearing potential) for at least 24 consecutive months
 (i.e., has had menses at any time in the preceding 24 consecutive months)

 -  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)