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

Trial Summary

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.

What data supports the effectiveness of the drug combination Venetoclax and BTK inhibitors for treating chronic lymphocytic leukemia?

Acalabrutinib, a next-generation BTK inhibitor, has shown safety and effectiveness in treating chronic lymphocytic leukemia (CLL) and is approved for this use. Ibrutinib, another BTK inhibitor, has significantly improved CLL treatment outcomes, and combining it with venetoclax has shown promising early results in clinical trials. ^{1 2 3 4 5}

Is the combination of Venetoclax and BTK inhibitors safe for treating chronic lymphocytic leukemia?

Acalabrutinib, a BTK inhibitor, is generally well-tolerated in patients with chronic lymphocytic leukemia, especially those who are intolerant to ibrutinib, another BTK inhibitor. Common side effects include diarrhea, headache, and cough, with serious side effects like neutropenia (low white blood cell count) and thrombocytopenia (low platelet count) occurring less frequently. ^{1 6 7 8 9}

What makes the drug combination of Venetoclax and BTK inhibitors unique for treating chronic lymphocytic leukemia?

The combination of Venetoclax and BTK inhibitors like Acalabrutinib and Ibrutinib is unique because it targets two different proteins involved in cancer cell survival, potentially offering a more effective treatment for chronic lymphocytic leukemia, especially in patients who have relapsed or are resistant to other treatments. ^{10 11 12 13 14}

What is the purpose of this trial?

This is a single center, open-label, phase II study of venetoclax (ABT-199) added to ibrutinib or acalabrutinib in patients with high-risk CLL who have received at least 12 months of ibrutinib or acalabrutinib monotherapy. The study will estimate the therapeutic efficacy of venetoclax consolidation in patients who have detectable CLL after receiving ibrutinib or acalabrutinib for at least 12 months and who have high risk CLL.

Research Team

Alessandra Ferrajoli, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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, 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 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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Assessing the pharmacokinetics of acalabrutinib in the treatment of chronic lymphocytic leukemia. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2023]

3. England pubmed.ncbi.nlm.nih.gov

ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]

5. England pubmed.ncbi.nlm.nih.gov

The evolving role of Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia. [2021]

6. United States 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. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. [2021]

11. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Ibrutinib and Venetoclax for First-Line Treatment of CLL. [2023]

13. England 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. [2022]

14. England pubmed.ncbi.nlm.nih.gov

Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. [2021]