The purpose of the study is to investigate whether the combination of venetoclax and ibrutinib (administered up to 840 mg per day) might be useful for the treatment of CLL or SLL that is not responding or no longer responding to treatment with ibrutinib alone. The study will evaluate whether this regimen can reduce the amount of cancerous cells in your body. If you agree, you will receive ibrutinib at a dose of up to 840 mg a day by mouth, as well as venetoclax. Although both of these agents are approved by the FDA for the treatment of CLL or SLL, the combination and the dosing schedule of ibrutinib are considered experimental.

This is phase 1 study for patients with CLL or small lymphocytic lymphoma (SLL) experiencing disease progression on single ibrutinib. This study will evaluate the optimal ibrutinib dose (including doses higher than 420 mg) when combined with venetoclax

During the screening period, patients will continue on ibrutinib at their previous tolerated dose, unless required to stop (e.g.: by a preceding clinical trial).

On cycle 1, day 1, the dose of ibrutinib will be assigned based on the dose cohort. Patients in cohort 1 will receive ibrutinib 420 mg PO daily. Patients in cohort 2 will receive ibrutinib 560 mg PO daily. Cohort 3 will be 840 mg PO daily.

On cycle 1, day 1, patients will initiate venetoclax. The dose of venetoclax will ramp-up from 20 mg PO daily to 400 mg PO daily over a 5 week period.

The primary safety endpoint is determination of DLTs during the first 35 days (completion of dose ramp up). The primary efficacy endpoint of overall response rate will be assessed on approximately Cycle 7, Day 1.

Rationale: The optimal management of patients that progress on ibrutinib, including those with acquired Btk or PLCg2 mutations, is not determined. In other cancers, continued treatment with small molecule inhibitors beyond disease progression provides significant benefit, with additional agents or adjustments to ablate the resistant subclone. Venetoclax is approved for the treatment of patients with CLL, and is well-tolerated and effective in high-risk disease, and so is an appropriate agent for this trial.

Inclusion Criteria:

• Clinical and phenotypic verification of B cell CLL or SLL and measurable disease.
• 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 their treatment course.
• 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.
• Adequate hematologic, hepatic and renal function

Exclusion Criteria:

• Known CNS lymphoma or leukemia
• History of Richter's or prolymphocytic transformation.
• Primary ibrutinib resistance
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura (ITP)
• 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.
• Active clinically significant cardiovascular disease or history of myocardial infarction within 6 months of first dose.
• 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.
• Pregnant or breast-feeding women
• Current infection requiring parenteral antibiotics.
• 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).