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

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)