Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Ohio State University Comprehensive Cancer Center
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
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.
Detailed 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.
Investigators
Kerry Rogers
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
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)
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:
Arms & Interventions
Treatment (venetoclax, ibrutinib)
Participants receive venetoclax PO daily on days 1-28 and ibrutinib PO 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 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.
Intervention: Ibrutinib
Treatment (venetoclax, ibrutinib)
Participants receive venetoclax PO daily on days 1-28 and ibrutinib PO 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 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.
Intervention: Laboratory Biomarker Analysis
Treatment (venetoclax, ibrutinib)
Participants receive venetoclax PO daily on days 1-28 and ibrutinib PO 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 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.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax
Time Frame: Up to 3 years
The rate of mutation negative status will be the percentage of patients who have negative testing for ibrutinib resistance mutations in the peripheral blood and bone marrow after 12 courses of combination ibrutinib and venetoclax treatment. Mutation negative status is defined as 1% variant allele frequency by the clinical grade test for mutation.
Secondary Outcomes
- Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib(Up to 3 years)
- Overall survival after beginning venetoclax in combination with ibrutinib(From start date of combination therapy up to 3 years)
- Progression-free survival after adding venetoclax to ibrutinib(From start date of combination therapy up to 3 years)
- Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment.(Up to 3 years)