Zanubrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Recruiting at 5 trial locations

Overseen By DFCI Clinical Trials Hotline

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of two drugs, zanubrutinib and venetoclax, in treating individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have previously received treatment. The trial includes three groups: those who have never used similar drugs, those who have used similar drugs without disease progression, and those whose disease worsened while on similar drugs. It suits individuals with CLL or SLL who have undergone prior treatment and meet specific criteria regarding past drug use and disease status. Participants must also be able to take oral medication and have adequate organ function. As a Phase 2 trial, the 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 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.

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

Previous studies have shown that zanubrutinib has a manageable safety profile. Researchers found it safer than ibrutinib, another treatment for chronic lymphocytic leukemia (CLL), with fewer severe side effects. In real-world use, people taking zanubrutinib reported some side effects, but these were generally not life-threatening.

Venetoclax, another CLL treatment, has also been well-studied. Clinical trials showed good results, with many patients responding well. However, about 34% of patients experienced serious side effects. Despite this, only a few patients had fatal reactions unrelated to disease progression.

Various studies have explored both zanubrutinib and venetoclax, and their safety profiles are considered manageable. Patients considering joining the trial can find reassurance in these findings, but discussing personal risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Zanubrutinib and Venetoclax for treating Chronic Lymphocytic Leukemia (CLL) because it offers a fresh approach compared to existing therapies. Most treatments for CLL involve chemotherapy or monoclonal antibodies, which can come with significant side effects and limited effectiveness for some patients. Zanubrutinib is a next-generation BTK inhibitor that precisely targets and blocks the protein driving cancer cell growth, potentially reducing side effects. Venetoclax, on the other hand, is a BCL-2 inhibitor that encourages cancer cells to undergo programmed death. This dual-target strategy might provide a more effective and tailored treatment option for CLL patients, especially those who haven't responded well to other therapies.

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

This trial will evaluate the combination of zanubrutinib and venetoclax for Chronic Lymphocytic Leukemia (CLL). Research has shown that zanubrutinib can be highly effective for treating CLL and SLL, with a 5-year progression-free survival rate of 72.2% in patients with certain genetic traits and an overall response rate of 97.3%. Studies have also found that zanubrutinib outperforms some other treatments when the disease returns or does not respond to the initial treatment.

Venetoclax is another strong option, particularly for those who have tried other treatments. Data shows high response rates of 75% and long-lasting effects in patients with relapsed or stubborn CLL. Overall survival rates for those who used venetoclax as the first treatment or after other treatments are very high, ranging from 91% to 100%. Together, these drugs show promise for effectively managing CLL and SLL in this trial. ^{3 6 7 8 9}

Who Is on the Research Team?

Inhye Ahn

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 agree to use birth control during the study.

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

Ability to understand and the willingness to sign a written informed consent document

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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, 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 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]

Citations

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

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6624969/

Efficacy of venetoclax in relapsed chronic lymphocytic ... In this pooled analysis of 4 clinical trials, high response rates (75%) and CR rates (22%) were seen with venetoclax in a population of predominantly heavily ...

3. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00070-6/fulltext

Activity of venetoclax in patients with relapsed or refractory ... These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic ...

4. cllsociety.org cllsociety.org/2024/02/outcomes-of-venetoclax-treatment-for-cll-patients/

Outcomes of Venetoclax Treatment for CLL Patients Overall survival after two years was 91% in the first-line therapy group and 100% in the relapsed with no previous BTKi group. Outcomes for ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12381400/

Real-World Safety and Efficacy of Venetoclax in Chronic ... Treating chronic lymphocytic leukemia (CLL) with the BCL-2 inhibitor venetoclax has shown favorable results in randomized clinical trials (RCTs).

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40881613/

Real-World Safety and Efficacy of Venetoclax in Chronic ... Treating chronic lymphocytic leukemia (CLL) with the BCL-2 inhibitor venetoclax has shown favorable results in randomized clinical trials (RCTs) ...

7. venclextahcp.com venclextahcp.com/cll/side-effects/ven-r-safety-profile.html

VEN+R Safety Data for CLL/SLL - venclexta Fatal adverse reactions that occurred in the absence of disease progression and within 30 days of venetoclax treatment were reported in 2% of patients in the ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1856/528978/Outcomes-with-Venetoclax-Based-Treatment-in

Outcomes with Venetoclax-Based Treatment in Patients with ... Venetoclax + rituximab resulted in a 2-year progression-free survival estimate of 85% in the mostly 2nd-line, post-chemotherapy setting of the MURANO clinical ...

9. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Across all the treatment groups, similar overall survival at 3 years was observed — 95.3%, 96.3%, 96.5%, and 95.0% in the venetoclax– ...