Obinutuzumab and High-Dose Ibrutinib in Treating Patients with Progressive Chronic Lymphocytic Leukemia

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent
• Clinical and phenotypic verification of B cell CLL or small lymphocytic lymphoma (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)
• 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 their 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
• Patients must have progressive disease Progression is based on 2008 iwCLL definition (Hallek et al, Blood 2008), 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 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; AND
• 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; OR
• 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); AND
• 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 >= 20 mg 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 child-bearing 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