Venetoclax + BTK Inhibitors for Chronic Lymphocytic Leukemia

Overseen By Philip Thompson, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Ibrutinib, Acalabrutinib

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Richter transformation, Active malignancy, 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: 6

Duration: 96 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how adding venetoclax to ibrutinib or acalabrutinib affects individuals with chronic lymphocytic leukemia (CLL), a cancer that impacts white blood cells. The researchers aim to determine if this combination better controls CLL in patients who still have the disease after taking ibrutinib or acalabrutinib alone for at least a year. The study seeks participants who have used one of these medications for 12 months but still have measurable CLL, which may include symptoms like swollen lymph nodes or high white blood cell counts. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you have been on ibrutinib or acalabrutinib for at least 12 months, so you will not need to stop these medications. However, you must not use warfarin, strong CYP3A inhibitors, or strong CYP3A inducers within 7 days of starting venetoclax.

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

Research has shown that using venetoclax with ibrutinib is a promising treatment for chronic lymphocytic leukemia (CLL). Studies have found this combination effective for patients who have tried other treatments. Most patients tolerate this treatment without major issues.

Adding venetoclax to ibrutinib can lead to some side effects, such as low blood cell counts and infections, but these are usually manageable with proper care.

Acalabrutinib, another drug in the trial, has been tested in similar situations. It is generally well-tolerated, though it can cause side effects like headaches or bruising, with serious issues being rare.

Overall, while some side effects may occur, the treatment is considered safe. Patients often find that the benefits outweigh the risks, especially when other treatments have not been successful. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Venetoclax with BTK inhibitors like Acalabrutinib and Ibrutinib for treating Chronic Lymphocytic Leukemia (CLL) because it offers a unique approach to combating cancer cells. Unlike standard treatments, which often target single pathways, this combination therapy simultaneously disrupts multiple pathways crucial for cancer cell survival and proliferation. Venetoclax specifically targets and inhibits the BCL-2 protein, which is vital for cancer cell survival, while Acalabrutinib and Ibrutinib inhibit Bruton's tyrosine kinase (BTK), disrupting signals necessary for the growth of CLL cells. This multi-pronged attack could lead to more effective and durable responses in patients, potentially offering a new and potent option for those with CLL.

What evidence suggests that this trial's treatments could be effective for high-risk CLL?

In this trial, participants will receive a combination of venetoclax, ibrutinib, and acalabrutinib. Studies have shown that adding venetoclax to ibrutinib can be very effective for people with chronic lymphocytic leukemia (CLL), especially those at high risk. This combination has led to better outcomes, such as higher survival rates, for some patients. Research also suggests that using venetoclax after ibrutinib benefits those who have been on ibrutinib for a while, aiming to attack cancer cells more effectively. While both ibrutinib and acalabrutinib work well individually, combining them with venetoclax might offer extra benefits. Overall, this combination shows promise in improving CLL treatment. ^{1 2 4 5 6}

Who Is on the Research Team?

Alessandra Ferrajoli, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with high-risk Chronic Lymphocytic Leukemia (CLL) who've had at least a year of Ibrutinib or Acalabrutinib treatment. They should be relatively healthy, with good kidney and liver function, no severe heart issues, and able to follow the study plan. Pregnant women can't join, nor those with other active cancers or infections.

Inclusion Criteria

I am not pregnant and agree to use effective birth control during and 30 days after treatment.

I have been on ibrutinib or acalabrutinib for over a year for my CLL.

My heart is functioning well.

Exclusion Criteria

I have not had severe bleeding in the last 3 weeks.

I have not consumed grapefruit, Seville oranges, or star fruit in the last 7 days.

I cannot take medications by mouth due to a digestive condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax, ibrutinib, and acalabrutinib. Treatment repeats every 4 weeks for up to 24 cycles.

96 weeks

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

6-12 months

Follow-up visits every 6-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Ibrutinib
• Venetoclax

Trial Overview The trial is testing if adding Venetoclax to ongoing Ibrutinib or Acalabrutinib therapy improves outcomes for CLL patients who haven't fully responded after 12 months of treatment. It's an open-label phase II study where everyone knows what treatments are given.

How Is the Trial Designed?

Group I: Treatment (venetoclax, ibrutinib, acalabarutinib) Experimental Treatment 3 Interventions

Patients receive venetoclax PO QD and ibrutinib PO QD and acalabrutinib PO BID. Treatment repeat every 4 weeks for up to 24 cycles in the absence of disease progression or unaccepted toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

Acalabrutinib, a next-generation BTK inhibitor, has shown improved safety and efficacy in treating chronic lymphocytic leukemia (CLL) compared to the first-in-class drug ibrutinib, with completed phase 3 trials demonstrating better outcomes for both relapsed/refractory and treatment-naive patients.

The drug selectively inhibits BTK with fewer off-target effects, and early studies suggest that combining acalabrutinib with other therapies, like a CD20 antibody and venetoclax, can lead to high rates of undetectable minimal residual disease in patients, indicating a potential for fixed-duration treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the pharmacokinetics of acalabrutinib in the treatment of chronic lymphocytic leukemia. Miao, Y., Xu, W., Li, J.[2022]

Ibrutinib, the first BTK inhibitor, is effective for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but can cause significant adverse events (AEs) like atrial fibrillation and bleeding, leading to discontinuation in 4%-26% of patients.

Acalabrutinib, a second-generation BTK inhibitor, has a more favorable safety profile with headaches being the most common AE (22%-51% of patients), and a low incidence of atrial fibrillation, making it a promising alternative for CLL and MCL treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice. O'Brien, SM., Brown, JR., Byrd, JC., et al.[2021]

In a phase 2 trial involving 45 patients with relapsed or refractory chronic lymphocytic leukaemia, 76% achieved undetectable minimal residual disease (uMRD) after a triple therapy regimen of obinutuzumab, acalabrutinib, and venetoclax, indicating promising efficacy.

Despite the high rate of uMRD, the trial did not meet the predefined activity threshold, suggesting that further research is needed to evaluate the benefits of this triple therapy compared to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Cramer, P., Fürstenau, M., Robrecht, S., et al.[2022]

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 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 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]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

Ibrutinib has significantly improved treatment outcomes for chronic lymphocytic leukemia (CLL), showing superior efficacy compared to other treatments in multiple phase III trials involving various patient populations, including relapsed/refractory and frontline settings.

The second-generation BTK inhibitor acalabrutinib appears to have a better safety profile with less off-target toxicity, and early trials suggest that combining BTK inhibitors with other therapies like venetoclax may optimize treatment strategies for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia. Gordon, MJ., Danilov, AV.[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]

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]

Zanubrutinib, a next-generation BTK inhibitor, shows promising efficacy in treating chronic lymphocytic leukemia (CLL) with minimal off-target effects compared to ibrutinib, which is known for its adverse events due to off-target kinase inhibition.

A Phase III study is underway to directly compare the safety and effectiveness of zanubrutinib against ibrutinib in patients with relapsed or refractory CLL, highlighting the potential for zanubrutinib to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Hillmen, P., Brown, JR., Eichhorst, BF., 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]

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 is a highly selective Bruton tyrosine kinase (BTK) inhibitor that effectively reduces tumor burden and increases survival in mouse models of chronic lymphocytic leukemia (CLL).

In two different mouse models, acalabrutinib demonstrated significant antitumor effects by decreasing the activation of key signaling molecules and showed greater BTK selectivity compared to ibrutinib, indicating its potential as a more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia. Herman, SEM., Montraveta, A., Niemann, CU., et al.[2021]

Citations

1. 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 ... Ibrutinib plus venetoclax may offer meaningful clinical advantages over acalabrutinib plus venetoclax with patients more likely to achieve higher rates of ...

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

Ibrutinib and venetoclax in combination for chronic ... The ibrutinib-venetoclax combination demonstrated promising effectiveness in patients with TP53 abnormalities, although outcomes remain less ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11913176/

Venetoclax consolidation in high-risk CLL treated with ... This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature.

4. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000347

Ibrutinib and venetoclax in combination for chronic ... The ibrutinib-venetoclax combination demonstrated promising effectiveness in patients with TP53 abnormalities, although outcomes remain less favorable than ...

5. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 Indication. VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02717611

NCT02717611 | A Study of ACP-196 (Acalabrutinib) in ... A Multicenter, Open-Label, Phase 2 study evaluating the efficacy and safety of Acalabrutinib in subjects with relapsed/refractory CLL (N=60) who are intolerant ...