A Phase 2 interventional study of Ibrutinib and Venetoclax in Chronic Lymphocytic Leukemia and Loss of Chromosome 17p, sponsored by Kerry Rogers. Withdrawn. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2021-11-05.
Sponsored by Kerry Rogers · Phase 2, Interventional, and Treatment
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.
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.
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Exclusion Criteria:
History of active malignancies other than CLL within the past 3 years prior to study entry, with the exception of:
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.
Drug: Ibrutinib · Drug: Venetoclax
Given PO
Also known as: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765
Given PO
Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta
Overall response rate (ORR) (intervention cohort)
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.
Time frame: After 12 cycles of combination therapy, assessed up to 3 years
Rate of mutation negative status (intervention cohort)
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.
Time frame: After 12 cycles of combination therapy, assessed up to 3 years
Incidence of BTK C481S mutations (observation cohort)
Person-time incidence of developing a BTK C481S mutation will be calculated by dividing the number of new mutations observed while on ibrutinib therapy by the total number of months patients are receiving ibrutinib and were at risk.
Time frame: Up to 3 years
Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)
Will be calculated in the observation cohort from the date a BTK C481S mutation was first reported until the date of clinical disease progression by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria or death from any cause, whichever occurs first.
Time frame: Up to 3 years
PFS after adding venetoclax to ibrutinib (intervention cohort)
PFS will be calculated in the intervention cohort from the start date of combination therapy (C1D1) until the date of progressive disease or death from any cause. Will be described using the method of Kaplan-Meier.
Time frame: Up to 3 years
Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)
OS will be calculated in the intervention cohort from the start date of combination therapy (C1D1) until the date of progressive disease or death from any cause. Will be described using the method of Kaplan-Meier.
Time frame: Up to 3 years
Incidence of adverse events (intervention cohort)
Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 with the exception of hematologic adverse events. Adverse events will be summarized by type, severity and perceived attribution. Hematologic adverse events will be graded according to CLL-specific criteria described in the IWCLL 2018 guidelines. The maximum grade for each type of toxicity will be recorded for each patient and frequency tables will be reviewed to determine the toxicity patterns. In addition, will also summarize the number of patients who discontinue combination therapy due to adverse events.
Time frame: Up to 3 years
Patient and disease characteristics associated with clinical disease progression (observation cohort)
Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.
Time frame: Up to 3 years
Changes in allelic frequency of ibrutinib resistance mutations after their development (observation cohort)
Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.
Time frame: Up to 3 years
Changes in allelic frequency of ibrutinib resistance mutations after addition of venetoclax (intervention cohort)
Univariable and multivariable analysis will be performed to determine what patient and disease characteristics are associated with development of ibrutinib resistance mutations. All standard CLL risk characteristics, prior treatments, and standard patient demographic information will be included.
Time frame: Up to 3 years
Novel resistance mechanisms to ibrutinib and ibrutinib/venetoclax combination therapy by whole exome and ribonucleic acid (RNA) sequencing (Seq)
For RNA-Seq data analysis, will first use FASTQC for the read quality recalibration, and then conduct removing, trimming, and filtering based on base quality scores and nucleotide distributions. Coverage BED (bedtools package) will be used for counting reads per feature per sample. Filtering of noise level counts across comparison groups will be used to reduce false positives. After filtering, differential expression will be tested using R package limma with voom normalization.
Time frame: At baseline and at clinical relapse, assessed up to 3 years
BH3 profiling
Correlate with response to combination venetoclax and ibrutinib therapy. Descriptive statistics such as mean, standard deviation, median, range, etc., for continuous variables and proportions for discrete variables will be used to summarize correlative endpoints in each of the defined strata. Graphical summaries will also be used extensively to visualize the data and describe relationships between variables (e.g. boxplots of BH3 profiling by response status).
Time frame: Up to 3 years
No study locations are listed for this record.
Plan to share: No
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Kerry Rogers