A Multicenter Study of Ibrutinib Resistance Development and Intervention With Venetoclax (Phase II)
Overview
- Phase
- Phase 2
- Intervention
- Ibrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Kerry Rogers
- Primary Endpoint
- Overall response rate (ORR) (intervention cohort)
- Status
- Withdrawn
- Last Updated
- 4 years ago
Overview
Brief Summary
This phase II trial studies how well the combination of ibrutinib and venetoclax works in treating patients with chronic lymphocytic leukemia whose cancer has stopped responding to ibrutinib alone. Both ibrutinib and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ibrutinib and venetoclax together after development of ibrutinib resistance may work better than discontinuing ibrutinib and switching to other chemotherapy drugs.
Detailed Description
PRIMARY OBJECTIVES: I. Overall response rate to combination ibrutinib and venetoclax after 12 cycles (intervention cohort). II. Rate of mutation negative status after 12 cycles of combination venetoclax and ibrutinib (intervention cohort ). SECONDARY OBJECTIVES: I. Incidence of BTK C481S mutations during ibrutinib treatment (observation cohort). II. Progression-free survival after development of a BTK C481S mutation (observation cohort). III. Progression-free and overall survival after adding venetoclax to ibrutinib (intervention cohort). IV. Type and incidence of adverse events during combination ibrutinib and venetoclax treatment in this patient population (intervention cohort). EXPLORATORY OBJECTIVES: I. Determine patient and disease characteristics associated with clinical disease progression in a univariable and multivariable analysis (observation cohort). II. Determine the changes in the allelic frequency of ibrutinib resistance mutations after their development (observation cohort) and after venetoclax is added (intervention cohort). III. Determine novel resistance mechanisms to ibrutinib and ibrutinib/venetoclax combination therapy by whole exome and ribonucleic acid (RNA) sequencing at baseline and clinical relapse. IV. Perform BH3 profiling and correlate with response to combination venetoclax and ibrutinib therapy. OUTLINE: This is a dose-escalation study of venetoclax. OBSERVATION COHORT: Patients who are taking ibrutinib enter Observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort. INTERVENTION COHORT: Patients receive venetoclax orally (PO) daily and ibrutinib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve minimal residual disease (MRD) negative complete remission (CR) after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients 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 by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
- •Currently taking ibrutinib and first took ibrutinib \> 12 months ago.
- •At high risk for the development of ibrutinib resistance. Patients are considered at high risk for ibrutinib resistance if they have had \>= 2 prior therapies for CLL prior to ibrutinib and have either del(17p)(13.1) and/or a complex CLL karyotype.
- •Able to continue taking ibrutinib.
- •Willing to enter the intervention cohort if clinical disease progression as defined by IWCLL 2018 criteria develops.
- •Eastern Cooperative Oncology Group (ECOG) performance status =\<
- •Absolute neutrophil count (ANC) \>= 1000/mm\^3 independent of growth factor support.
- •Platelets \>= 100,000/mm\^3 or \>= 50,000/mm\^3 if bone marrow involvement independent of transfusion support in either situation.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x upper limit of normal (ULN).
- •Total bilirubin =\< 1.5 x ULN unless bilirubin rise is due to Gilbert?s syndrome or of non-hepatic origin.
Exclusion Criteria
- •Inability to continue taking ibrutinib for any reason.
- •Presence of a known ibrutinib resistance mutation as defined.
- •Clinical disease progression while taking ibrutinib as defined by IWCLL 2018 criteria.
- •Major surgery or a wound that has not fully healed within 4 weeks of randomization.
- •Known central nervous system lymphoma.
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
- •Requires chronic treatment with strong CYP3A inhibitors.
- •Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
- •Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection.
- •Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
Arms & Interventions
Treatment (venetoclax, ibrutinib)
OBSERVATION COHORT: Patients who are taking ibrutinib enter observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort. INTERVENTION COHORT: Patients receive venetoclax PO daily and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negative CR after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
Intervention: Ibrutinib
Treatment (venetoclax, ibrutinib)
OBSERVATION COHORT: Patients who are taking ibrutinib enter observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort. INTERVENTION COHORT: Patients receive venetoclax PO daily and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negative CR after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Outcomes
Primary Outcomes
Overall response rate (ORR) (intervention cohort)
Time Frame: After 12 cycles of combination therapy, assessed up to 3 years
Defined as the percentage of patients who have achieved any response better than stable disease after 12 cycles of combination ibrutinib and venetoclax treatment. All eligible patients who take one study dose of venetoclax will be considered evaluable and included in the denominator when calculating the ORR. ORR will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.
Rate of mutation negative status (intervention cohort)
Time Frame: After 12 cycles of combination therapy, assessed up to 3 years
Rate of mutation negative status will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.
Secondary Outcomes
- Incidence of BTK C481S mutations (observation cohort)(Up to 3 years)
- Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)(Up to 3 years)
- Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)(Up to 3 years)
- PFS after adding venetoclax to ibrutinib (intervention cohort)(Up to 3 years)
- Incidence of adverse events (intervention cohort)(Up to 3 years)