Venetoclax and Ibrutinib in Patients With Relapsed/Refractory CLL or SLL

This is an open-label non-randomized two-center phase 2 study evaluating the safety and efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or refractory CLL/SLL.

The primary objective of this study is to evaluate the efficacy of concurrent therapy with ibrutinib and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

The secondary objectives of this study are to define the safety, tolerability, and dose-limiting toxicity (DLT) within 28 days of completion of dose-escalation.

Eligibility Criteria:
Inclusion Criteria:

* Subject must voluntarily sign and date an informed consent approved by the Institutional Review Board prior to initiation of any study specific procedures
* Subject must have a diagnosis of CLL that meets International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute (NCI)-Working Group (WG) criteria
* Subject must have relapsed/refractory disease with an indication for treatment according to the 2008 IWCLL/NCI WG criteria
* Measurable nodal disease by computed tomography (CT)
* Absolute neutrophil count \> 750 cells/mm\^3 (0.75 x 10\^9/L)
* Platelet count \> 30,000 cells/mm\^3 (30 x 10\^9/L)
* Hemoglobin \> 8.0 g/dL
* Serum aspartate transaminase (AST) or alanine transaminase (ALT) =\< 2.5 x upper limit of normal (ULN)
* Estimated creatinine clearance \>= 30 mL/min (Cockcroft-Gault)
* Bilirubin =\< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
* Prothrombin time/international normalized ratio (PT/INR) \< 1.5 x ULN and partial thromboplastin time (PTT) (activated \[a\]PTT) \< 1.5 x ULN
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
* Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for \>= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon study entry
* Male and female subjects must agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug

Exclusion Criteria:

* Subject has previously received either venetoclax or ibrutinib
* Subject has received a live virus vaccine within 28 days prior to the initiation of study treatment
* Subject has undergone an allogeneic stem cell transplant in the past 1 year and must not have active chronic graft versus host disease (cGVHD) if over 1 year post allogeneic transplant
* Subject has developed Richter's transformation confirmed by biopsy
* Chemotherapy =\< 21 days prior to first administration of study treatment and/or monoclonal antibody =\< 6 weeks prior to first administration of study treatment
* History of other malignancies, except:

  * Malignancy treated with curative intent and with no known active disease present for \>= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  * Adequately treated carcinoma in situ without evidence of disease
* Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc, or chronic administration \[\> 14 days\] of \> 20 mg/day of prednisone) within 28 days of the first dose of study drug
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
* Recent infection requiring systemic treatment that was completed =\< 14 days before the first dose of study drug
* Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version \[v\]4), grade =\< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
* Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
* History of stroke or intracranial hemorrhage within 6 months prior to enrollment
* Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV); subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
* Any uncontrolled active systemic infection
* Major surgery within 4 weeks of first dose of study drug
* Any life threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
* Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
* Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
* Concomitant use of warfarin or other vitamin K antagonists
* Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
* Lactating or pregnant
* Unwilling or unable to participate in all required study evaluations and procedures
* Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)