Venetoclax and Ibrutinib in Treating in Participants With Chronic Lymphocytic Leukemia and Ibrutinib Resistance Mutations
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|ClinicalTrials.gov Identifier: NCT03513562|
Recruitment Status : Recruiting
First Posted : May 1, 2018
Last Update Posted : March 28, 2019
|Condition or disease||Intervention/treatment||Phase|
|Chronic Lymphocytic Leukemia Ibrutinib Resistance||Drug: Ibrutinib Other: Laboratory Biomarker Analysis Drug: Venetoclax||Phase 2|
I. Determine if the addition of venetoclax to ibrutinib therapy can eliminate ibrutinib resistance mutations.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||28 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL|
|Actual Study Start Date :||February 27, 2019|
|Estimated Primary Completion Date :||February 28, 2021|
|Estimated Study Completion Date :||February 28, 2021|
Experimental: 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.
Other: Laboratory Biomarker Analysis
- 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.
- Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib [ Time Frame: Up to 3 years ]Rate of minimal residual disease negative complete remission estimated with a 95% exact binomial at the response assessment after 12 courses of therapy.
- Progression-free survival after adding venetoclax to ibrutinib [ Time Frame: From start date of combination therapy up to 3 years ]Progression-free survival (PFS) calculated from the start date of combination therapy until the date of clinical disease progression by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria or death from any cause, whichever occurs first. PFS described using the method of Kaplan-Meier. Median PFS reported with 95% confidence interval.
- Overall survival after beginning venetoclax in combination with ibrutinib [ Time Frame: From start date of combination therapy up to 3 years ]Overall survival (OS) calculated from the start date of combination therapy until the date of death from any cause, censoring patients alive at last follow-up. OS described using the method of Kaplan-Meier. Median OS reported with 95% confidence interval.
- Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment. [ Time Frame: Up to 3 years ]Safety and tolerability of the combination regimen adverse events are summarized by type, severity and perceived attribution according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with the exception of hematologic adverse events
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03513562
|Contact: The Ohio State University Comprehensive Cancer Center||800-293-5066||OSUCCCClinicaltrials@osumc.edu|
|Contact: Jennifer Zvosecfirstname.lastname@example.org|
|United States, Ohio|
|Ohio State University Comprehensive Cancer Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Kerry A. Rogers, MD 614-366-9338 email@example.com|
|Principal Investigator: Kerry A. Rogers, MD|
|Principal Investigator:||Kerry Rogers, MD||Ohio State University Comprehensive Cancer Center|