BTKi + Venetoclax for Chronic Lymphocytic Leukemia

(Benefit VA Trial)

Recruiting at 3 trial locations

Overseen By Murali K Nittala, MBBS MS MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Office of Research and Development

Must be taking: BTKi

Must not be taking: Heparin, Warfarin, Strong CYP3A inhibitors, Strong CYP3A inducers

Disqualifiers: Richter's transformation, Prolymphocytic leukemia, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding venetoclax to the current treatment with BTKi pills (such as ibrutinib, acalabrutinib, or zanubrutinib) is more effective for individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The study will compare continuing with only BTKi pills to combining them with venetoclax for one year, after which both medications will be stopped to monitor the results. Ideal participants are those diagnosed with CLL or SLL who are currently on BTKi treatment without disease progression. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must stop taking warfarin at least 10 days before joining. Also, you should not be on strong CYP3A4/5 inhibitors or inducers, and you cannot take more than 20 mg of prednisone daily.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining BTKi drugs, such as ibrutinib, acalabrutinib, or zanubrutinib, with venetoclax is generally easy for patients to handle. In previous studies, patients often found this combination more manageable than more aggressive treatments like chemoimmunotherapy.

For instance, a study on acalabrutinib and venetoclax found that many patients tolerated the treatment well. Another study with ibrutinib and venetoclax supported this finding. Both studies reported no significant increase in serious side effects when these drugs were used together.

Common side effects might include mild issues like tiredness or diarrhea, which are typical for this type of treatment. Overall, past research indicates that the treatment seems safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining BTK inhibitors like Acalabrutinib, Ibrutinib, and Zanubrutinib with Venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because this approach targets the disease differently than current treatments. Standard CLL treatments typically involve chemotherapy or targeted therapies alone, but this combination aims to disrupt two critical pathways simultaneously, potentially leading to better outcomes. BTK inhibitors block a protein essential for cancer cell survival, while Venetoclax promotes cancer cell death by targeting BCL-2 proteins. This dual mechanism could offer more effective control of the disease and possibly reduce the treatment duration, which is a significant advancement over existing options.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that using Bruton Tyrosine Kinase Inhibitors (BTKi) like ibrutinib, acalabrutinib, or zanubrutinib with venetoclax can effectively treat chronic lymphocytic leukemia (CLL). In this trial, one group of participants will receive the combination of BTKi and venetoclax for 12 cycles before discontinuing. Studies have found that adding venetoclax to BTKi treatment slows cancer progression, preventing it from worsening quickly. Early results suggest this combination might be more beneficial than using BTKi alone. Another group in this trial will continue with BTKi as a single agent. Researchers aim to determine if this treatment can provide lasting benefits even after stopping the medication. ^{1 3 6 7 8}

Who Is on the Research Team?

Suman Kambhampati, MD MBBS

Principal Investigator

Kansas City VA Medical Center, Kansas City, MO

Are You a Good Fit for This Trial?

This trial is for veterans with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who are already responding to treatment with a BTK inhibitor. Specific eligibility criteria were not provided, but typically participants must meet certain health standards and may be required to have specific characteristics related to their condition.

Inclusion Criteria

Low TLS risk

I have been diagnosed with CLL or SLL.

My blood tests or scans show signs of CLL/SLL.

Exclusion Criteria

I do not have severe heart failure, unstable chest pain, or uncontrolled heart rhythm problems.

I have had Richter's transformation or prolymphocytic leukemia.

I am currently on blood thinners like heparin or warfarin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BTKi alone or BTKi plus Venetoclax for 12 cycles

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24-36 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Ibrutinib
• Venetoclax
• Zanubrutinib

Trial Overview The study is testing whether adding venetoclax, another type of medication for CLL/SLL, to the current treatment with a BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) improves outcomes. Participants will either continue their current BTKi alone or receive it in combination with venetoclax for one year.

How Is the Trial Designed?

Group I: Arm B : BTKi + Venetoclax for 12 cycles, then discontinue Experimental Treatment 2 Interventions

BTKi + Venetoclax for 12 cycles, then discontinue Experimental Intervention

Group II: Arm A : Continue BTKi single agent Active Control 1 Intervention

Continue BTKi single agent (monotherapy) Standard Intervention

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

In a phase 3 trial involving 652 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib demonstrated superior progression-free survival compared to ibrutinib, with a hazard ratio of 0.65, indicating a significant reduction in the risk of disease progression or death.

Zanubrutinib also had a better safety profile than ibrutinib, resulting in fewer adverse events that led to treatment discontinuation, particularly fewer cardiac events, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown, JR., Eichhorst, B., Hillmen, P., et al.[2023]

Acalabrutinib, a selective BTK inhibitor, was well tolerated in patients with chronic lymphocytic leukemia (CLL) who previously discontinued ibrutinib due to adverse events, with 72% of ibrutinib-related side effects not recurring.

The treatment showed a high overall response rate of 76%, with a 1-year progression-free survival rate of 83.4%, indicating its efficacy in managing CLL in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Awan, FT., Schuh, A., Brown, JR., et al.[2021]

Acalabrutinib, a selective BTK inhibitor, was found to be effective in treating 73% of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were intolerant to ibrutinib, with a median follow-up of 35 months showing promising survival rates.

The most common side effects of acalabrutinib included diarrhea and headache, but it was generally well tolerated, making it a suitable alternative for patients who cannot continue with ibrutinib due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Rogers, KA., Thompson, PA., Allan, JN., et al.[2021]

In a study of 23 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), BTK inhibitors (ibrutinib and zanubrutinib) were found to provide durable disease control after patients progressed on venetoclax, with a median progression-free survival of 34 months.

Patients who had a prior remission duration of 24 months or longer and those who achieved complete remission on venetoclax experienced significantly longer progression-free survival after starting BTK inhibitors, highlighting the importance of previous treatment response in predicting outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Lin, VS., Lew, TE., Handunnetti, SM., et al.[2021]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

In a study involving 127 patients with relapsed or refractory chronic lymphocytic leukaemia who had previously been treated with ibrutinib, 65% showed an overall response to venetoclax, indicating its effectiveness as a treatment option for those who did not respond to ibrutinib.

Venetoclax was found to have a favorable safety profile, with no treatment-related deaths reported, although common side effects included neutropenia and thrombocytopenia, which were observed in a significant number of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Jones, JA., Mato, AR., Wierda, WG., et al.[2021]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

The combination of venetoclax and obinutuzumab has been approved as a superior first-line treatment for elderly, unfit patients with chronic lymphocytic leukaemia (CLL), showing better efficacy than chlorambucil/obinutuzumab based on a phase-III trial.

For patients with high-risk features like deletion 17p or TP53 mutations, targeted therapies such as ibrutinib or venetoclax/obinutuzumab are recommended due to their poor response to traditional chemotherapy, highlighting the importance of personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. Cramer, P., von Tresckow, J., Eichhorst, B., et al.[2021]

In a phase 2 study involving 80 previously untreated high-risk and older patients with chronic lymphocytic leukemia (CLL), the combination of ibrutinib and venetoclax resulted in a high response rate, with 88% achieving complete remission after 12 cycles of treatment.

The treatment was well-tolerated, with an adverse-event profile similar to that of the individual drugs, although three patients experienced tumor lysis syndrome, indicating the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib and Venetoclax for First-Line Treatment of CLL. Jain, N., Keating, M., Thompson, P., et al.[2023]

Citations

1. ashpublications.org ashpublications.org/ashclinicalnews/news/8257/Where-to-Start-BTK-Inhibitors-or-Venetoclax-as

Where to Start: BTK Inhibitors or Venetoclax as Initial Therapy ... Three covalent BTKis have been approved to treat CLL: zanubrutinib, acalabrutinib, and ibrutinib. Treatment with BTKis continues indefinitely and involves ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7039

Comparison of outcomes for patients (pts) with R/R chronic ... Background: Pts with R/R CLL/SLL who failed BTKi and venetoclax have limited treatment (tx) options and poor prognoses. FDA approval of ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39049159/

Real-world comparative effectiveness of venetoclax ... In this real-world study, VenO was associated with better effectiveness outcomes than BTKi-based regimens in 1 L CLL.

4. jnj.com jnj.com/media-center/press-releases/significant-efficacy-benefit-of-imbruvica-ibrutinib-plus-venetoclax-versus-acalabrutinib-plus-venetoclax-in-frontline-treatment-of-patients-with-chronic-lymphocytic-leukaemia-suggested-by-indirect-treatment-comparison

Significant efficacy benefit of IMBRUVICA® (ibrutinib) plus ... Cross-study findings indicate significant clinical benefit of frontline fixed-duration ibrutinib plus venetoclax with improved likelihood of ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2409804

Fixed-Duration Acalabrutinib Combinations in Untreated ... Acalabrutinib–venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40944848/

Indirect Comparisons of the Efficacy and Safety ... Introduction: Compared with chemoimmunotherapy, both zanubrutinib monotherapy and venetoclax plus obinutuzumab prolong progression-free survival ...

7. ashpublications.org ashpublications.org/bloodneoplasia/article/1/3/100034/517258/Ibrutinib-and-venetoclax-in-combination-for

Ibrutinib and venetoclax in combination for chronic ... The combination of ibrutinib and venetoclax has emerged as a promising therapeutic strategy for patients with chronic lymphocytic leukemia (CLL).

8. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000645

Real-world safety profile of therapy with ibrutinib or ... Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial