SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03943342

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Multicenter Study of Ibrutinib Resistance Development and Intervention With Venetoclax (Phase II)

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.

NCT03943342 Chronic Lymphocytic Leukemia Loss of Chromosome 17p
MeSH: Leukemia Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell
HPO: Chronic lymphatic leukemia Leukemia Lymphoid leukemia

2 Interventions

Name: Ibrutinib

Description: Given PO

Type: Drug

Treatment (venetoclax, ibrutinib)

Name: Venetoclax

Description: Given PO

Type: Drug

Treatment (venetoclax, ibrutinib)


Primary Outcomes

Description: 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.

Measure: Overall response rate (ORR) (intervention cohort)

Time: After 12 cycles of combination therapy, assessed up to 3 years

Description: 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.

Measure: Rate of mutation negative status (intervention cohort)

Time: After 12 cycles of combination therapy, assessed up to 3 years

Secondary Outcomes

Description: 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.

Measure: Incidence of BTK C481S mutations (observation cohort)

Time: Up to 3 years

Description: 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.

Measure: Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)

Time: Up to 3 years

Description: 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.

Measure: PFS after adding venetoclax to ibrutinib (intervention cohort)

Time: Up to 3 years

Description: 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.

Measure: Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)

Time: Up to 3 years

Description: 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.

Measure: Incidence of adverse events (intervention cohort)

Time: Up to 3 years

Other Outcomes

Description: 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.

Measure: Patient and disease characteristics associated with clinical disease progression (observation cohort)

Time: Up to 3 years

Description: 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.

Measure: Changes in allelic frequency of ibrutinib resistance mutations after their development (observation cohort)

Time: Up to 3 years

Description: 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.

Measure: Changes in allelic frequency of ibrutinib resistance mutations after addition of venetoclax (intervention cohort)

Time: Up to 3 years

Description: 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.

Measure: Novel resistance mechanisms to ibrutinib and ibrutinib/venetoclax combination therapy by whole exome and ribonucleic acid (RNA) sequencing (Seq)

Time: At baseline and at clinical relapse, assessed up to 3 years

Description: 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).

Measure: BH3 profiling

Time: Up to 3 years

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 C481S

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.. Incidence of BTK C481S mutations (observation cohort). --- C481S ---

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.. Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort). --- C481S ---

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.. Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort). --- C481S --- --- C481S ---

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.. PFS after adding venetoclax to ibrutinib (intervention cohort). --- C481S ---

SECONDARY OBJECTIVES: I. Incidence of BTK C481S mutations during ibrutinib treatment (observation cohort). --- C481S ---

Progression-free survival after development of a BTK C481S mutation (observation cohort). --- C481S ---



HPO Nodes


HPO:
Chronic lymphatic leukemia
Genes 8
SAMHD1 RNASEH2B ADAR RNASEH2A IFIH1 RNASEH2C TREX1 PIK3R1
Leukemia
Genes 125
MPL RNASEH2B KRAS NPM1 TET2 MYD88 TSR2 RPL26 RPL27 TREX1 EFL1 PIGL SCN11A FLT3 PMS2 RPL35A EVC2 ABL1 CEBPA RARA NRAS WAS WIPF1 ATRX SH2B3 PDGFRA RB1 RNASEH2A PDGFRB CALR ARHGAP26 SH3GL1 RPS7 RPS10 NUMA1 GATA1 GATA2 RPS15A APC NSD1 ETV6 TCIRG1 DNAJC21 EVC SRP54 RPS17 NBN RPS19 SAMHD1 MSH2 RPS24 NUP214 RPS26 RPS27 RPS28 RPS29 MLLT10 RUNX1 XRCC4 CBFB CBL BCR ADAR TRIP13 ADA2 NSUN2 CREBBP PICALM GFI1 F13A1 F13B FANCA FANCC BLM FANCD2 FANCE NUTM1 JAK2 IFIH1 TYROBP MSH6 FANCG LIG4 PTPN11 SAMD9L THPO NF1 STS PIGA BRCA2 DYNC2LI1 PIK3CA SBDS GLI1 PIK3R1 BRD4 SETBP1 RNASEH2C LPP BUB1 BUB1B SCN9A SCN10A TREM2 MLF1 MLH1 ELANE DKC1 ATM HAX1 RPL35 GNB1 BUB3 CEP57 TAL1 KIT TAL2 RPL5 EP300 TP53 RPL11 KIF11 RPL15 DNMT3A RPL18
Lymphoid leukemia