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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2019-02511 | Registry Identifier | CTRP (Clinical Trial Reporting Program) |
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Study not feasible
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| Name | Class |
|---|---|
| Janssen Research & Development, LLC | INDUSTRY |
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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment (venetoclax, ibrutinib) | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ibrutinib | Drug | Given PO |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | After 12 cycles of combination therapy, assessed up to 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 3 years |
| Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 3 years |
Inclusion Criteria:
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.
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
History of lymphoma (Richter?s syndrome) unless in complete remission > 2 years without relapse.
History of active malignancies other than CLL within the past 3 years prior to study entry, with the exception of:
Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.).
Prior allogeneic stem cell transplant with Day 0 < 12 months prior and/or with chronic graft versus host disease (GVHD) requiring current use of immunosuppression. Patients with prior allogeneic stem cell transplant with Day 0 > 12 months prior who do not require immunosuppression for GVHD will be eligible.
Patients in the observation cohort who develop clinical disease progression and do NOT have a known ibrutinib resistance mutation will be taken off study and may not enter the intervention cohort.
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| Name | Affiliation | Role |
|---|---|---|
| Kerry A Rogers, MD | Ohio State University Comprehensive Cancer Center | Principal Investigator |
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| Label | URL |
|---|---|
| The Jamesline | View source |
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| ID | Term |
|---|---|
| D015451 | Leukemia, Lymphocytic, Chronic, B-Cell |
| C538045 | Chromosome 17 deletion |
| ID | Term |
|---|---|
| D015448 | Leukemia, B-Cell |
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| C551803 | ibrutinib |
| C579720 | venetoclax |
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| Venetoclax | Drug | Given PO |
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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. |
| 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. | 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. | 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. | 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. | 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. | 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. | 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). | Up to 3 years |
| D009369 |
| Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |