Venetoclax and Ibrutinib in Treating Patients with Progressive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent
• Clinical and phenotypic verification of B cell CLL or SLL and measurable disease. Immunophenotyping of the leukemic cells (blood, lymph node, or bone marrow) must demonstrate a monoclonal (or light chain positive) B cell population with immunophenotype consistent with CLL (e.g.: co-expressing CD19, CD5, and CD23)
• Prior therapy: Patients must have been receiving single agent ibrutinib therapy at the time of disease progression. Patient may have received other therapy in combination with ibrutinib earlier in the treatment course. Patients may have received other therapies after ibrutinib but stopped based on the defined wash-out periods and still meet iwCLL criteria for treatment
• Disease Status: Patients must have progressive disease. Progression is based on 2008 iwCLL definition but excluding patients who have treatment related lymphocytosis as the sole progressive factor. Therefore, patients must have at least one of the following: * >= 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be >= 2 cm); appearance of new palpable lymph nodes * >= 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not previously present * Decrease in hemoglobin >= 2 gm/dL, or decrease >= 50% in platelet or granulocyte count with a bone marrow biopsy showing CLL cell infiltrate * Progressive lymphocytosis, >= 50% higher than lowest absolute blood lymphocyte count (ALC) on single agent ibrutinib therapy, excluding ibrutinib treatment-related lymphocytosis * If receiving ibrutinib as part of a clinical trial: meets criteria for disease progression based on trial defined criteria
• Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. Sexually active men and women of child-bearing potential must use highly effective contraceptives (e.g., condoms, implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or sterilized partner) while on study; this should be maintained for 30 days after the last dose of study drug for females and 90 days for males. If a female subject or the partner of a male subject becomes pregnant, the sponsor must be notified. Male subjects should refrain from sperm donation for 90 days after the last dose of study drug
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Adequate hematologic function (platelet and absolute neutrophil count [ANC] values in accordance with ongoing ibrutinib studies for patients with CLL), unless cytopenias are due to bone marrow highly infiltrated with CLL cells, e.g. > 80%
• Platelet count >= 30,000/uL
• Absolute neutrophil count >= 500 /uL
• Prothrombin time (PT), partial thromboplastin time (PTT) =< 1.5 times upper limit of normal
• Serum creatinine < 1.5 times institutional upper limit of normal
• Calculated creatinine clearance (CrCl) >= 40 mL/min (based upon the Cockcroft-Gault Equation)
• Total bilirubin =< 1.5 times upper limit of normal (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)
• Alanine aminotransferase (ALT) =< 1.5 times upper limit of normal

Exclusion Criteria

• Known central nervous system (CNS) lymphoma or leukemia
• History of Richter’s or prolymphocytic transformation
• Primary ibrutinib resistance, defined by progressive disease within the first 2 months of first initiating ibrutinib therapy
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP)
• CLL therapy, with the exception of ibrutinib within the following timeframes: * Chemotherapy, external beam radiation therapy, anticancer antibodies within 30 days prior to the first dose of drug on this study * Corticosteroid use >= 20mg prednisone within 1 week prior to first dose on this study * Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose on this study * Allogeneic stem cell transplant within 6 months prior to first dose on this study
• History of major surgery within 4 weeks prior to first dose on this study
• History of prior malignancy, with the exception of adequately treated non-melanoma skin cancer, malignancies treated with curative intent and with no evidence of active disease for more than 3 years, or adequately treated cervical carcinoma in situ without current evidence of disease
• Currently active clinically significant cardiovascular disease or history of myocardial infarction within 6 months of first dose
• Serologic status and/or polymerase chain reaction (PCR) testing reflecting active hepatitis B or C infection
• Known history of infection with human immunodeficiency virus (HIV)
• Unable to swallow capsules or disease significantly affecting gastrointestinal function
• History of stroke or intracranial hemorrhage within 6 months of first dose
• Requires anticoagulation with warfarin or other vitamin K antagonists
• Requires treatment with a strong cytochrome P(CYP)450 3A inhibitor OR subjects who have received a strong cytochrome P(CYP)450 3A inhibitor within 7 days prior to the first dose of ibrutinib or subjects who require continuous treatment with a strong CYP 450 3A inhibitor
• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. Women of childbearing age must obtain a pregnancy test and pregnant or breast feeding females are excluded
• Patients who are currently receiving another investigational therapy are excluded
• Current infection requiring parenteral antibiotics
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
• Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child Pugh classification
• Patients who require immediate cytoreduction due to high risk of tumor lysis syndrome (ie, absolute lymphocyte count greater than 100k/uL)