Chronic Lymphocytic LeukemiaPhase 2NCT03513562
Venetoclax and Ibrutinib in Treating in Participants With Chronic Lymphocytic Leukemia and Ibrutinib Resistance Mutations
A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and Venetoclax in people with Chronic Lymphocytic Leukemia and Ibrutinib Resistance, run by Ohio State University Comprehensive Cancer Center at 1 site in United States.
Trial summary
This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia, Ibrutinib Resistance
- What is being tested?
- Ibrutinib, Laboratory Biomarker Analysis and Venetoclax
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- 26 Mar 2019to 31 Dec 2026
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the World Health Organization (WHO) classification of hematologic disorders or International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Currently taking ibrutinib and first took ibrutinib > 3 months ago
- Presence of a known ibrutinib resistance mutation at ≥ 4% variant allele frequency OR < 4% with two separate measurements at least 4 weeks apart with increasing variant allele frequency
- Adequate bone marrow function independent of growth factor support at screening unless clearly due to marrow involvement by CLL and/or disease-related immune thrombocytopenia; if cytopenias are due to disease in the bone marrow any degree of cytopenias are allowed; patients with active uncontrolled autoimmune cytopenias are excluded
- Hemoglobin ≥ 8 g/dL
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- Absolute neutrophil count (ANC) ≥ 1,000/mm^3
- Platelets ≥ 40,000/mm^3
- Prothrombin time/partial thromboplastin time (PT/PTT) ≤ 1.5 x upper limit of normal (ULN) (unless receiving anticoagulation)
- Total bilirubin ≤ 1.5 x ULN (excepting Gilbert's syndrome)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ≤ ULN
- Creatinine clearance ≥ 40 mL/min/1.73m^2
- Using 24-hour creatinine clearance or modified Cockcroft-Gault equation
- All patients must practice a highly effective method of birth control
- Able to take an absorb pill form oral medications
- Ability to understand and sign a written informed consent
Who cannot join
- Inability to continue taking ibrutinib for any reason
- Treatment with chemotherapy, immunotherapy, radiotherapy, targeted small molecule inhibitors, biologic agents, and/or an investigational therapy for 5 half-lives prior to first study dose of venetoclax; treatment with a biologic agent, such as a monoclonal antibody, for 30 days prior to study treatment; treatment with ibrutinib is allowed
- Need for anticoagulation with a vitamin K antagonist (warfarin); other anticoagulants and antiplatelet agents are allowed
- Treatment with a moderate or strong cytochrome P450 3A4 (CYP3A) inhibitor or inducer within 7 days prior to first dose of venetoclax or need for treatment with a strong CYP3A inhibitor or inducer during the period or the study; patients who have a need for treatment with a moderate CYP3A inhibitor or inducer during venetoclax dose escalation will also be excluded
- Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
- History of lymphoma (Richter's syndrome) unless in complete remission > 2 years without relapse
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- Known active involvement of the central nervous system by lymphoma or leukemia
- Known infection with the human immunodeficiency (HIV) virus
- A cardiovascular disability status of New York Heart Association Class ≥ 2, defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain
- Positive hepatitis serology:
- Patients with positive serology for hepatitis B defined as positivity for hepatitis B virus surface antigen measurement (HBsAg) or anti-hepatitis B core total antibodies (antiHBc) may be considered for inclusion in the study on a case-by-case basis if they are hepatitis B viral deoxyribonucleic acid (DNA) negative and are willing to undergo ongoing hepatitis B virus (HBV) DNA testing by real-time polymerase chain reaction (PCR) monthly during the study
- Patients with positive hepatitis B surface antigen (HBsAg) consistent with prior vaccination to HBV (i.e., hepatitis B immune status/anti-hepatitis B surface antibody [anti-HBs+], anti-HBc-) may participate
- Patients suspected to have false positive serologic studies because of intravenous (IV) immunoglobulin administration are potentially eligible without need for further monitoring if they have negative PCR studies for viral DNA/RNA after discussion with the principal investigator
- Patients with positive hepatitis C serology are excluded unless they have negative hepatitis C virus (HCV) ribonucleic acid (RNA) testing after receiving HCV-specific treatment and the case is discussed with the principal investigator
- Female patients who are pregnant, breast-feeding, or planning to become pregnant
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- History of active malignancies other than chronic lymphocytic leukemia (CLL) within the past 3 years prior to study entry, with the exception of:
- Adequately treated in situ carcinoma or the cervix or breast
- Basal cell or localized squamous cell carcinoma of the skin
- Previous malignancy treated with curative therapy and not expected to relapse
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
About this study
Official title: Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL
This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Venetoclax and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Read the detailed description
PRIMARY OBJECTIVES:
- Determine if the addition of venetoclax to ibrutinib therapy can eliminate ibrutinib resistance mutations.
SECONDARY OBJECTIVES:
- 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.
- Conditions
- Chronic Lymphocytic Leukemia, Ibrutinib Resistance
- Being tested
- Ibrutinib, Laboratory Biomarker Analysis, Venetoclax
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbrutinibDrug
Also called BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765
Given PO
Laboratory Biomarker AnalysisOther
Correlative studies
VenetoclaxDrug
Also called ABT-0199, ABT-199, ABT199, GDC-0199
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (venetoclax, ibrutinib) | Experimental | 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. Receives: Drug: Ibrutinib; Other: Laboratory Biomarker Analysis; Drug: Venetoclax |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax
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.
Measured: Up to 3 years
Secondary outcomes (4)
Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib
Rate of minimal residual disease negative complete remission estimated with a 95% exact binomial at the response assessment after 12 courses of therapy.
Measured: Up to 3 years
Progression-free survival after adding venetoclax to ibrutinib
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.
Measured: From start date of combination therapy up to 3 years
Overall survival after beginning venetoclax in combination with ibrutinib
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.
Measured: From start date of combination therapy up to 3 years
Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment.
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
Measured: Up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2018
- Study start26 Mar 2019
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Lymphocytic LeukemiaStudies of the same condition, open and under way.
- More trials run by Ohio State University Comprehensive Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kerry Rogers, Ohio State University Comprehensive Cancer Center
- Investigators
- Kerry Rogers, MD, Principal investigator, Ohio State University Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03513562
- Sponsor's protocol ID
- OSU-17387
- Other IDs
- NCI-2018-00410
- Status last verified
- Feb 2026
- First submitted
- 19 Apr 2018
- Last updated
- 6 Feb 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Study of Venetoclax Added to Ibrutinib to Eliminate Ibrutinib Resistance Mutations in CLL
- ClinicalTrials.gov ID
- NCT03513562
- Acronym / sponsor ID
- OSU-17387
- Conditions
- Chronic Lymphocytic Leukemia, Ibrutinib Resistance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Ohio State University Comprehensive Cancer CenterUniversity, hospital or other
- Study start
- 26 Mar 2019 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 1 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial studies how well venetoclax and ibrutinib work in treating participants with chronic lymphocytic leukemia and have developed genetic mutations after previously being treated with ibrutinib. Venetoclax and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES:
- Determine if the addition of venetoclax to ibrutinib therapy can eliminate ibrutinib resistance mutations.
SECONDARY OBJECTIVES:
- 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (venetoclax, ibrutinib) | Experimental | Drug: Ibrutinib, Other: Laboratory Biomarker Analysis, Drug: VenetoclaxParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established in the World Health Organization (WHO) classification of hematologic disorders or International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Currently taking ibrutinib and first took ibrutinib > 3 months ago
- Presence of a known ibrutinib resistance mutation at ≥ 4% variant allele frequency OR < 4% with two separate measurements at least 4 weeks apart with increasing variant allele frequency
- Adequate bone marrow function independent of growth factor support at screening unless clearly due to marrow involvement by CLL and/or disease-related immune thrombocytopenia; if cytopenias are due to disease in the bone marrow any degree of cytopenias are allowed; patients with active uncontrolled autoimmune cytopenias are excluded
Key exclusion criteria (22 listed)
- Inability to continue taking ibrutinib for any reason
- Treatment with chemotherapy, immunotherapy, radiotherapy, targeted small molecule inhibitors, biologic agents, and/or an investigational therapy for 5 half-lives prior to first study dose of venetoclax; treatment with a biologic agent, such as a monoclonal antibody, for 30 days prior to study treatment; treatment with ibrutinib is allowed
- Need for anticoagulation with a vitamin K antagonist (warfarin); other anticoagulants and antiplatelet agents are allowed
- Treatment with a moderate or strong cytochrome P450 3A4 (CYP3A) inhibitor or inducer within 7 days prior to first dose of venetoclax or need for treatment with a strong CYP3A inhibitor or inducer during the period or the study; patients who have a need for treatment with a moderate CYP3A inhibitor or inducer during venetoclax dose escalation will also be excluded
- Uncontrolled autoimmune hemolytic anemia or thrombocytopenia
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IbrutinibAlso: BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Given PO | Drug | Treatment (venetoclax, ibrutinib) |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Treatment (venetoclax, ibrutinib) |
| VenetoclaxAlso: ABT-0199, ABT-199, ABT199, GDC-0199Given PO | Drug | Treatment (venetoclax, ibrutinib) |
Primary outcome
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.
4 secondary outcomes
Rate of minimal residual disease negative complete remission after 12 courses of venetoclax and ibrutinib
Time frame: Up to 3 years
Progression-free survival after adding venetoclax to ibrutinib
Time frame: From start date of combination therapy up to 3 years
Overall survival after beginning venetoclax in combination with ibrutinib
Time frame: From start date of combination therapy up to 3 years
Discontinuation rate due to adverse events with combination venetoclax and ibrutinib treatment.
Time frame: Up to 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2026.
- The JameslineLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kerry Rogers, MD principal investigator
Ohio State University Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ibrutinib, Laboratory Biomarker Analysis and Venetoclax in people with Chronic Lymphocytic Leukemia and Ibrutinib Resistance, run by Ohio State University Comprehensive Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 6 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of mutation negative status after 12 courses of combination therapy of ibrutinib and venetoclax (time frame: Up to 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2026.