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

Trial Summary

What is the purpose of this trial?

People who have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) are often treated with ibrutinib, acalabrutinib, or zanubrutinib. These are pills that are taken by mouth. This type of pill is called "Bruton Tyrosine Kinase Inhibitor" or BTKi. Another treatment for CLL/SLL is a different pill called venetoclax. The purpose of this study is to compare continuing the current treatment with BTKi alone, as long as it is working, to another arm of treatment which adds venetoclax to the current treatment (BTKi), for one year. After one year, both pills in this arm of treatment would be stopped and the participants will be closely monitored.

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Ibrutinib, and Venetoclax for treating Chronic Lymphocytic Leukemia?

Research shows that the combination of ibrutinib and venetoclax has been effective in treating chronic lymphocytic leukemia, with studies indicating a potential synergistic effect when used together. Additionally, BTK inhibitors like ibrutinib and zanubrutinib have shown effectiveness in patients with CLL who are resistant to venetoclax. ^{1 2 3 4 5}

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

The combination of BTK inhibitors like acalabrutinib and venetoclax has been found to be generally safe for treating chronic lymphocytic leukemia, with common mild side effects including diarrhea, headache, and cough. More serious side effects, though less common, can include neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and infections. ^{6 7 8 9 10}

How is the drug combination of BTKi and Venetoclax unique for treating chronic lymphocytic leukemia?

The combination of BTK inhibitors (like Acalabrutinib, Ibrutinib, and Zanubrutinib) with Venetoclax is unique because it targets two different pathways in cancer cells, potentially offering a more effective treatment for chronic lymphocytic leukemia, especially in patients who have not responded well to other treatments. This approach can be particularly beneficial for those who have relapsed or are resistant to single-agent therapies. ^{1 3 4 11 12}

Research Team

Suman Kambhampati, MD MBBS

Principal Investigator

Kansas City VA Medical Center, Kansas City, MO

Eligibility Criteria

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

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

I have been diagnosed with CLL or SLL.

Exclusion Criteria

I have had Richter's transformation or prolymphocytic leukemia.

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

I am currently on blood thinners like heparin or warfarin.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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]

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]

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]

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]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Chemoimmunotherapy in the First-Line Treatment of Chronic Lymphocytic Leukaemia: Dead Yet, or Alive and Kicking? [2021]

3. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

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

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

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

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

6. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]

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

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

9. Italy pubmed.ncbi.nlm.nih.gov

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

10. United States 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. [2021]

11. 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]

12. Germany pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. [2021]