Venetoclax and Ibrutinib in Treating Patients With Chronic or Small Lymphocytic Leukemia

PRIMARY OBJECTIVES:

I. Estimate therapeutic activity (best response [complete response (CR)/complete response
with incomplete recovery (CRi)]) of combined ibrutinib and venetoclax in patients with
chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL).

SECONDARY OBJECTIVES:

I. To determine the safety of this combination strategy. II. To estimate the time to best
response with this combination. III. To determine the progression-free survival (PFS) and
overall survival (OS).

IV. To test pharmacodynamic endpoints and molecular interactions between these two drugs.

V. To assess the therapeutic activity (best response [CR/CRi]) in subgroups of patients
defined by IGHV mutation or fluorescence in situ hybridization (FISH) subtype.

TERTIARY OBJECTIVES:

I. To study immunological and molecular changes in the peripheral blood and the bone marrow
in response to ibrutinib and venetoclax.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Beginning on day 1 of
course 4, patients also receive venetoclax PO QD on days 1-28. Treatment repeats every 28
days for up to 27 courses in the absence of disease progression or unacceptable toxicity.
Patients with residual disease or who are positive for minimal residual disease (MRD) after
course 27 may continue treatment with ibrutinib.

Inclusion Criteria:

- Patients with a diagnosis of CLL/SLL who are refractory to and/or relapsed after at
least one prior therapy will be eligible (cohort 1); untreated patients with high-risk
features (del(17p), or mutated TP53, or del(11q), or unmutated immunoglobulin heavy
chain variable [IGHV], or >= 65 years of age) are eligible (cohort 2) provided they
have active disease requiring treatment as defined by the International Working Group
for CLL (IWCLL)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with
Gilbert's disease (in patients [pts] with elevated total bilirubin due to increased
indirect bilirubin, pts with direct bilirubin =< 1.5 x ULN are eligible)

- Creatinine clearance > 50 mL/min (calculated according to institutional standards or
using Cockcroft-Gault, Modification of Diet in Renal Disease [MDRD], or Chronic Kidney
Disease Epidemiology Collaboration [CKD-EPI] formula)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN,
unless clearly due to disease involvement

- Platelet count of greater than 20,000/mul, with no platelet transfusion in 2 weeks
prior to registration; this criteria is waived if the thrombocytopenia is due to bone
marrow involvement with the disease

- Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (beta-hCG) pregnancy test result within 7 days prior to the
first dose of study drugs and must agree to use an effective contraception method
during the study and for 30 days following the last dose of study drug; women of non-
childbearing potential are those who are postmenopausal greater than 1 year or who
have had a bilateral tubal ligation or hysterectomy; men who have partners of
childbearing potential must agree to use an effective contraceptive method during the
study and for 30 days following the last dose of study drug

- Free of prior malignancies for 2 years with exception of patients diagnosed with basal
cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or
breast, who are eligible even if they are currently treated or have been treated
and/or diagnosed in the past 2 years prior to study enrolment; if patients have
another malignancy that was treated within the last 2 years, such patients may be
enrolled if the likelihood of requiring systemic therapy for this other malignancy
within 2 years is less than 10%, as determined by an expert in that particular
malignancy at MD Anderson Cancer Center, and after consultation with the principal
investigator

- Patients or their legally authorized representative must provide written informed
consent

Exclusion Criteria:

- Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
investigational therapy within 3 weeks prior to the first dose of the study drugs

- Uncontrolled active systemic infection (viral, bacterial, and fungal)

- Known positive serology for human immunodeficiency virus (HIV), due to potential
drug-drug interactions between anti-retroviral medications and the study drugs

- Active hepatitis B infection (defined as the presence of detectable hepatitis B virus
[HBV] deoxyribonucleic acid [DNA], hepatitis B e [HBe] antigen or hepatitis B surface
[HBs] antigen); subjects with serologic evidence of prior vaccination (hepatitis B
surface antigen [HBsAg] negative, anti-HBs antibody positive, anti-hepatitis B core
[HBc] antibody negative) are eligible; patients who are HBsAg negative/hepatitis B
surface antibody (HBsAb) positive but hepatitis B core antibody (HBcAb) positive are
eligible, provided HBV DNA is negative

- Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in
plasma by polymerase chain reaction (PCR)

- Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune
thrombocytopenia) requiring steroid therapy with > 20 mg daily of prednisone dose or
equivalent

- Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias,
congestive heart failure, or myocardial infarction within 2 months of screening, or
any class 3 or 4 cardiac disease as defined by the New York Heart Association
Functional Classification

- Patient is pregnant or breast-feeding

- Concurrent use of warfarin

- Received strong (CYP3A) inhibitors or strong CYP3A inducers within 7 days of starting
study drugs

- Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days
of starting study drugs

- Prior treatment with venetoclax or ibrutinib

- Malabsorption syndrome or other condition that precludes enteral route of
administration

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risk associated
with study participation or investigational product administration or may interfere
with the interpretation of study results and/or would make the patient inappropriate
for enrollment into this study