Sonrotoclax + Zanubrutinib for Chronic Lymphocytic Leukemia

Recruiting at 43 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: BeiGene

Disqualifiers: Cardiovascular, Pulmonary, Malignancy, Infection, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 15 cycles

87 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to support the registration plan of sonrotoclax plus zanubrutinib treatment in participants with previously untreated CLL. This study is designed to assess the contribution of sonrotoclax to the efficacy outcome of the combination of zanubrutinib and sonrotoclax.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

What data supports the effectiveness of the drug Sonrotoclax + Zanubrutinib for Chronic Lymphocytic Leukemia?

Research shows that Zanubrutinib, a part of the treatment, is effective in treating chronic lymphocytic leukemia (CLL), with studies demonstrating improved progression-free survival and a high overall response rate in patients. It is also noted for its enhanced safety profile compared to other similar drugs. ^{1 2 3 4 5}

Is the combination of Sonrotoclax and Zanubrutinib safe for humans?

Zanubrutinib, a part of the treatment combination, has been studied in various trials and is generally well tolerated in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Common side effects include infections, bruising, and fatigue, with more serious effects like neutropenia (low white blood cell count) and pneumonia occurring less frequently. However, specific safety data for the combination of Sonrotoclax and Zanubrutinib is not provided in the available research. ^{1 3 4 6 7}

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

The combination of Sonrotoclax and Zanubrutinib is unique because it pairs a next-generation, selective Bruton tyrosine kinase inhibitor (Zanubrutinib) with another agent, potentially offering a novel mechanism of action that could enhance treatment effectiveness compared to existing therapies. Zanubrutinib has shown improved progression-free survival in CLL patients, and combining it with Sonrotoclax may provide a synergistic effect, similar to other successful drug combinations in CLL treatment. ^{1 2 3 8 9}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for adults over 18 with untreated Chronic Lymphocytic Leukemia (CLL) who need treatment. Participants should be relatively healthy, able to perform daily activities with ease or some effort, and have measurable disease via scans. They must have good marrow, liver, and kidney function, agree to birth control if applicable, understand the study protocol and consent to participate.

Inclusion Criteria

My kidney function is normal.

I have signed the consent form and can follow the study's requirements.

My cancer can be measured with a scan.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either sonrotoclax combined with zanubrutinib or zanubrutinib monotherapy. Combination therapy is administered for a fixed duration of 15 cycles.

15 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and response rates.

Up to 66 months

Long-term Follow-up

Participants are monitored for progression-free survival and overall survival.

Up to 66 months

Treatment Details

Interventions

• Sonrotoclax
• Zanubrutinib

Trial Overview The study is testing the effectiveness of combining Sonrotoclax with Zanubrutinib versus using Zanubrutinib alone in treating CLL. The goal is to see if adding Sonrotoclax improves outcomes for patients who haven't been treated before.

Participant Groups

Group I: Arm A: Combination Therapy: Sonrotoclax + Zanubrutinib Experimental Treatment 2 Interventions

Participants will receive sonrotoclax in combination with zanubrutinib daily for a fixed duration of 15 cycles.

Group II: Arm B: Monotherapy: Zanubrutinib Active Control 1 Intervention

Participants will receive zanubrutinib monotherapy daily until disease progression or unacceptable toxicity, whichever occurs first.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a phase 3 study involving 590 patients with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to bendamustine-rituximab, with a hazard ratio of 0.42, indicating a strong efficacy advantage.

Zanubrutinib demonstrated an acceptable safety profile, with fewer severe adverse events like neutropenia compared to bendamustine-rituximab, suggesting it could be a promising new treatment option for patients with CLL and SLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Tam, CS., Brown, JR., Kahl, BS., et al.[2023]

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 the phase 3 SEQUOIA trial involving adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to the standard treatment of bendamustine plus rituximab (BR).

Patients treated with zanubrutinib reported better health-related quality-of-life outcomes at 12 and 24 weeks, including improvements in global health status, physical functioning, and reduced symptoms of diarrhea, fatigue, and nausea/vomiting compared to those receiving BR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Ghia, P., Barnes, G., Yang, K., et al.[2023]

Zanubrutinib, a selective BTK inhibitor, was well-tolerated in a phase 1 study with 144 patients, showing no dose-limiting toxicities and achieving over 95% BTK occupancy in blood cells at all tested doses.

In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), zanubrutinib demonstrated a remarkable overall response rate of 96.2% and a 100% estimated progression-free survival at 12 months, indicating strong efficacy with low major toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Tam, CS., Trotman, J., Opat, S., et al.[2021]

Zanubrutinib (zanu) has been shown to significantly improve progression-free survival compared to bendamustine-rituximab in treatment-naive patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as a first-line treatment option.

In a direct comparison with ibrutinib, zanu demonstrated a better safety profile and enhanced clinical efficacy, leading to its approval by the FDA and EMA as a preferred treatment for CLL/SLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. Molica, S., Tam, C., Allsup, D., et al.[2023]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, was found to be generally well tolerated when combined with obinutuzumab in a phase 1 study involving 81 patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL).

The combination therapy showed high efficacy, achieving a 100% overall response rate in treatment-naïve CLL patients and a 92% response rate in relapsed/refractory CLL patients, with a 72% response rate in relapsed/refractory FL patients over a median follow-up of 20 to 29 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Tam, CS., Quach, H., Nicol, A., et al.[2021]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, showed a high overall response rate of 94.5% in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma carrying the del(17p) mutation, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with an estimated 18-month progression-free survival rate of 88.6% and an overall survival rate of 95.1%, although some patients experienced adverse events, including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Tam, CS., Robak, T., Ghia, P., et al.[2021]

In a murine model of chronic lymphocytic leukemia (CLL), the combination of ibrutinib and venetoclax showed greater efficacy than either drug alone, leading to deeper responses and longer-lasting effects due to reduced cell proliferation and increased apoptosis.

The combination treatment also positively altered the T-cell compartment, increasing naive T-cells and decreasing effector memory T-cells, although resistance to treatment eventually developed, linked to downregulation of BIM expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. Kater, AP., Slinger, E., Cretenet, G., et al.[2022]

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

References

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

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. [2023]

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

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

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

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]

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

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]

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

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]

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

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

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

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]