Zanubrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Recruiting at 5 trial locations

Overseen By Megan Forsyth

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jennifer R. Brown, MD, PhD

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS involvement, Cardiovascular disease, 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: 15 months

45 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to test the effectiveness of zanubrutinib in combination with venetoclax in participants with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that are moderate or strong CYP3A inhibitors or inducers, and you should consult with the trial team about any other medications you are taking.

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

Venetoclax has shown to be effective in treating chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in patients with relapsed or refractory CLL. Additionally, BTK inhibitors like Zanubrutinib have been effective in patients with CLL who are resistant to Venetoclax, suggesting potential benefits of combining these drugs. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?

Venetoclax, used in treating Chronic Lymphocytic Leukemia (CLL), has shown an acceptable safety profile in various studies, with common side effects including diarrhea, neutropenia (low white blood cell count), and nausea. Serious side effects like severe neutropenia are manageable with dose adjustments and supportive care. ^{1 2 3 4 6}

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

The combination of Zanubrutinib and Venetoclax is unique because it combines two oral drugs with different mechanisms: Zanubrutinib targets the Bruton tyrosine kinase (BTK) pathway, while Venetoclax inhibits the B-cell lymphoma 2 (BCL-2) protein, potentially offering a more comprehensive approach to treating chronic lymphocytic leukemia compared to using either drug alone. ^{2 3 4 7 8}

Research Team

Inhye Ahn

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who need therapy and have not used certain inhibitors. They must be in stable health, understand the study, agree to use contraception, and have no history of certain other diseases or recent treatments that could affect safety.

Inclusion Criteria

I am 18 years old or older.

I agree to use birth control during the study.

I can take care of myself but might not be able to do active work.

Exclusion Criteria

I have a serious heart condition that is currently affecting me.

I finished IV antibiotics for an infection less than a week ago or have an ongoing infection.

Pregnant women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib and venetoclax for 15 months

15 months

Re-treatment (optional)

Participants may receive an additional 12 months of re-treatment at the time of disease recurrence

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

Treatment Details

Interventions

• Venetoclax
• Zanubrutinib

Trial Overview The trial is testing the combination of two drugs, zanubrutinib and venetoclax, for their effectiveness against CLL/SLL in patients who've had previous treatment. It's designed to see how well these drugs work together after initial therapies.

Participant Groups

Group I: Cohort C: BTKi exposed and with disease progression Experimental Treatment 2 Interventions

Participants who experienced disease progression on a prior BTK inhibitor. Participants with BTK C481X mutation at enrollment will be excluded.

Group II: Cohort B: BTKi or BCL2i exposed without disease progression Experimental Treatment 2 Interventions

Participants who have received prior treatment with a BTK or BCL-2 inhibitor and discontinued treatment for any reason other than disease progression

Group III: Cohort A: BTKi and BCL2i naive Experimental Treatment 2 Interventions

Participants who have never received a BTK inhibitor or a BCL-2 inhibitor

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

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

Jennifer R. Brown, MD, PhD

Lead Sponsor

Trials

3

Recruited

140+

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[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]

Venetoclax, an oral BCL-2 inhibitor, is an effective long-term treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), particularly those with high-risk features like chromosome 17p deletion, based on a safety analysis of 350 patients.

The treatment is generally well tolerated, with manageable side effects; however, common adverse events included diarrhea (41%), neutropenia (40%), and nausea (39%), and serious infections occurred in 15% of patients, indicating the need for monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. Davids, MS., Hallek, M., Wierda, W., et al.[2019]

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 141 patients with chronic lymphocytic leukemia (CLL) treated with venetoclax, the overall response rate was 72%, indicating that venetoclax is an effective treatment option, especially for patients with mutations that typically resist other therapies like ibrutinib.

The treatment was generally well-tolerated, with 85% of patients reaching the maximum recommended dose of 400 mg daily, although some experienced adverse effects such as neutropenia (47.4%) and tumor lysis syndrome (13.4%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Mato, AR., Thompson, M., Allan, JN., et al.[2020]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. [2018]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

3. France pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]

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

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

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

Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia. [2019]

7. Austria pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. [2020]

8. Italy pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. [2020]