PRIMARY OBJECTIVES:
I. To estimate the therapeutic efficacy of venetoclax consolidation in patients who have
detectable chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) after
receiving ibrutinib monotherapy for at least 12 months and who have high risk CLL.
SECONDARY OBJECTIVES:
I. Determine complete remission (CR)/complete remission with incomplete hematologic recovery
(CRi) rate after 6, 12, 18 and 24 cycles of combination therapy and to estimate the time to
best response with this combination.
II. Determine the cumulative rate of bone marrow minimal residual disease (MRD)-free complete
responders by an assay method with at least 0.01% sensitivity and median time to
MRD-negativity.
III. Determine the safety of combined ibrutinib and venetoclax. IV. Determine the
progression-free and overall survival.
OUTLINE:
Participants receive venetoclax orally (PO) once daily (QD) and ibrutinib PO QD. Courses
repeat every 4 weeks for up to 24 courses in the absence of disease progression or unaccepted
toxicity.
After completion of study treatment, participants are followed up every 6-12 months.
Inclusion Criteria:
- Patients must have a diagnosis of CLL/SLL and EITHER have high-risk cytogenetic
features or molecular features, defined as: del(17p), del(11q), mutated TP53, complex
metaphase karyotype (defined as >=3 unrelated chromosomal abnormalities, present in at
least 2 metaphases on conventional, stimulated cytogenetic analysis) OR have developed
a BTK or PLCG2 mutation, detected by sequencing and have not developed disease
progression during ibrutinib therapy as defined by International Workshop on Chronic
Lymphocytic Leukemia (IWCLL) criteria OR B2M has not normalized after 1 year (y)
ibrutinib therapy and/or is elevated at the time of screening
- Note: some patients treated with ibrutinib may no longer have detectable
fluorescence in situ hybridization (FISH), karyotypic or molecular abnormalities
after 12 months of therapy. These patients will be eligible if they fulfill the
above criteria on a bone marrow biopsy or peripheral blood specimen taken within
the 3 months prior to starting ibrutinib or at some time during their ibrutinib
therapy and analyzed at a Clinical Laboratory Improvement Act (CLIA)-accredited
laboratory
- Patients must have received at least 12 months of ibrutinib therapy and have
measurable CLL by at least one of the following: Absolute monoclonal lymphocyte count
> 4000/microL; OR measurable lymph nodes with at least one node > 1.5 cm in diameter
on computed tomography (CT); OR Bone marrow with >= 30% lymphocytes or peripheral
blood specimen taken within the 3 months prior to starting ibrutinib or at some time
during their ibrutinib therapy and analyzed at a CLIA-accredited laboratory
- Patients must have received at least 12 months of ibrutinib therapy and have
measurable CLL by at least one of the following: Absolute monoclonal lymphocyte count
> 4000/microL; OR measurable lymph nodes with at least one node > 1.5 cm in diameter
on CT; OR bone marrow with >= 30% lymphocytes on aspirate differential; OR detectable
CLL cells using a standardized flow cytometry assay for minimal residual disease
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Serum bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with
Gilbert's disease
- Serum creatinine clearance of >= 50 ml/min (calculated or measured)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN,
unless clearly due to disease involvement
- Platelet count of greater than 20,000/ul, with no platelet transfusion in prior 2
weeks
- Absolute neutrophil count (ANC) >= 500/ul in the absence of growth factor support
unless due to compromised bone marrow production from CLL, indicated by >= 80% CLL in
marrow
- Hemoglobin >= 8mg/dL
- International normalized ratio (INR) < 1.5
- Absence of uncontrolled cardiac arrhythmia
- Echocardiogram demonstrating left ventricular ejection fraction (LVEF) >= 35%
- New York Heart Association (NYHA) functional class =< 2
- Ability to provide informed consent and adhere to the required follow-up
- Women of childbearing potential must have a negative serum or urine beta human
chorionic gonadotropin (beta-human chorionic gonadotropin [hCG]) pregnancy test result
within 7 days prior to the first dose of study drugs and must agree to use both a
highly effective method of birth control (e.g., implants, injectables, combined oral
contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized
partner) and a barrier method (e.g., condoms, vaginal ring, sponge, etc.) during the
period of therapy and for 30 days after the last dose of study drug. Women of non-
childbearing potential are those who are postmenopausal (defined as absence of menses
for >= 1 year) or who have had a bilateral tubal ligation or hysterectomy. Men who
have partners of childbearing potential must agree to use effective contraception,
defined above, during the study and for 30 days following the last dose of study drug
- Patients or their legally authorized representative must provide written informed
consent
Exclusion Criteria:
- Richter transformation
- Active malignancy requiring systemic therapy, other than CLL, with the exception of:
adequately treated in situ carcinoma of the cervix uteri; adequately treated basal
cell carcinoma or localized squamous cell carcinoma of the skin; previous malignancy
confined and surgically resected (or treated with other modalities) with curative
intent
- Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy,
experimental therapy within 3 weeks prior to the first dose of the study drug
- Grade 3 or 4 hemorrhage within the past 3 weeks
- Uncontrolled active infections (viral, bacterial, and fungal)
- Females who are pregnant or lactating
- Known positive serology for human immunodeficiency virus (HIV)
- Active hepatitis B infection (defined as the presence of detectable hepatitis B virus
[HBV] deoxyribonucleic acid [DNA] or hemoglobin E [HBe] antigen). Patients who are
hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive are
eligible, provided HBV DNA is negative. These patients must have monthly monitoring of
HBV DNA for the duration of the study.
- Active hepatitis C, defined by the detection of 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 > 20 mg prednisone daily or equivalent,
within 7 days of starting venetoclax
- Received other investigational therapeutic agent for CLL/SLL within 21 days of
starting venetoclax
- Concurrent use of warfarin
- Received strong CYP3A inhibitors or strong CYP3A inducers within 7 days of starting
venetoclax
- Consuming grapefruit, grapefruit products, Seville oranges, or star fruit within 7
days of starting venetoclax
- Prior treatment with venetoclax or other Bcl-2 inhibitor
- Malabsorption syndrome or other condition that precludes enteral route of
administration
