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About
This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Venetoclax and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Full description
PRIMARY OBJECTIVES:
I. Determine if the addition of venetoclax to ibrutinib therapy can eliminate ibrutinib resistance mutations.
SECONDARY OBJECTIVES:
I. Determine the rate of minimal residual disease negative complete remission to combination ibrutinib and venetoclax therapy.
II. Determine progression-free survival after the addition of venetoclax to ibrutinib.
III. Determine overall survival after the addition of venetoclax to ibrutinib. IV. Describe the toxicity profile of venetoclax in combination with ibrutinib in this patient population.
EXPLORATORY OBJECTIVES I. Describe changes in variant allele frequency (VAF) of known ibrutinib resistance mutations after the addition of venetoclax.
II. Perform BH3 profiling and correlate with response to combination venetoclax and ibrutinib therapy.
III. Determine if increased expression of MCL-1 and BCL-XL is a potential mechanism of resistance to venetoclax when given in combination with ibrutinib.
IV. Determine potential mechanisms of resistance to ibrutinib and venetoclax combination treatment by whole exome and ribonucleic acid (RNA) sequencing.
OUTLINE: This is a dose escalation study of venetoclax.
Participants receive venetoclax orally (PO) daily on days 1-28 and ibrutinib PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 or 24 courses in the absence of disease progression or unacceptable toxicity. Participants with minimal residual disease (MRD) negativity after 12 or 24 courses discontinue treatment, while participants with MRD positivity continue treatment with venetoclax in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, participants are followed up every 3 months for 2 years and then every 6 months thereafter.
Enrollment
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Inclusion criteria
Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the World Health Organization (WHO) classification of hematologic disorders or International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Currently taking ibrutinib and first took ibrutinib > 3 months ago
Presence of a known ibrutinib resistance mutation at ≥ 4% variant allele frequency OR < 4% with two separate measurements at least 4 weeks apart with increasing variant allele frequency
Adequate bone marrow function independent of growth factor support at screening unless clearly due to marrow involvement by CLL and/or disease-related immune thrombocytopenia; if cytopenias are due to disease in the bone marrow any degree of cytopenias are allowed; patients with active uncontrolled autoimmune cytopenias are excluded
Hemoglobin ≥ 8 g/dL
Absolute neutrophil count (ANC) ≥ 1,000/mm^3
Platelets ≥ 40,000/mm^3
Prothrombin time/partial thromboplastin time (PT/PTT) ≤ 1.5 x upper limit of normal (ULN) (unless receiving anticoagulation)
Total bilirubin ≤ 1.5 x ULN (excepting Gilbert's syndrome)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ≤ ULN
Creatinine clearance ≥ 40 mL/min/1.73m^2
All patients must practice a highly effective method of birth control
Able to take an absorb pill form oral medications
Ability to understand and sign a written informed consent
Exclusion criteria
Inability to continue taking ibrutinib for any reason
Treatment with chemotherapy, immunotherapy, radiotherapy, targeted small molecule inhibitors, biologic agents, and/or an investigational therapy for 5 half-lives prior to first study dose of venetoclax; treatment with a biologic agent, such as a monoclonal antibody, for 30 days prior to study treatment; treatment with ibrutinib is allowed
Need for anticoagulation with a vitamin K antagonist (warfarin); other anticoagulants and antiplatelet agents are allowed
Treatment with a moderate or strong cytochrome P450 3A4 (CYP3A) inhibitor or inducer within 7 days prior to first dose of venetoclax or need for treatment with a strong CYP3A inhibitor or inducer during the period or the study; patients who have a need for treatment with a moderate CYP3A inhibitor or inducer during venetoclax dose escalation will also be excluded
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
History of lymphoma (Richter's syndrome) unless in complete remission > 2 years without relapse
Known active involvement of the central nervous system by lymphoma or leukemia
Known infection with the human immunodeficiency (HIV) virus
A cardiovascular disability status of New York Heart Association Class ≥ 2, defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain
Positive hepatitis serology:
Female patients who are pregnant, breast-feeding, or planning to become pregnant
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
History of active malignancies other than chronic lymphocytic leukemia (CLL) within the past 3 years prior to study entry, with the exception of:
Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.)
Prior allogeneic stem cell transplant with day 0 < 12 months prior and/or with chronic graft versus host disease (GVHD) requiring current use of immunosuppression; patients with prior allogeneic stem cell transplant with day 0 > 12 months prior who do not require immunosuppression for GVHD will be eligible
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28 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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