Sonrotoclax + Zanubrutinib vs Venetoclax + Obinutuzumab for Chronic Lymphocytic Leukemia

Recruiting at 219 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: BeiGene

Disqualifiers: Previous CLL treatment, Prolymphocytic leukemia, CNS involvement, PML, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 48 weeks (12 cycles) for venetoclax plus obinutuzumab, 60 weeks (15 cycles) for sonrotoclax plus zanubrutinib

640 Participants Needed

Trial Summary

What is the purpose of this trial?

The main objective of this study is to compare the efficacy of sonrotoclax plus zanubrutinib versus venetoclax plus obinutuzumab in participants with chronic lymphocytic leukemia (CLL)

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 coordinators or your doctor.

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

Research shows that the drug combination of Venetoclax and Obinutuzumab is effective for treating Chronic Lymphocytic Leukemia (CLL). In the CLL14 trial, this combination led to longer progression-free survival and higher response rates compared to another treatment, chlorambucil plus obinutuzumab. It also maintained improvements in clinical outcomes during long-term follow-up. ^{1 2 3 4 5}

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

The combination of Venetoclax and Obinutuzumab has been shown to have an acceptable safety profile in treating chronic lymphocytic leukemia, with common side effects including neutropenia (a low level of white blood cells) and some infections, but no fatal infections were reported in first-line treatment. Most side effects can be managed with supportive care and dose adjustments. ^{1 2 4 5 6}

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

The combination of Sonrotoclax + Zanubrutinib is unique because it pairs a novel BCL2 inhibitor (Sonrotoclax) with a Bruton’s tyrosine kinase (BTK) inhibitor (Zanubrutinib), potentially offering a new mechanism of action compared to the established venetoclax + obinutuzumab regimen, which is already known for its chemotherapy-free approach and effectiveness in improving progression-free survival in chronic lymphocytic leukemia. ^{1 2 3 4 7}

Eligibility Criteria

This trial is for adults who haven't been treated for chronic lymphocytic leukemia (CLL) yet. They should be able to perform daily activities with ease or have only slight limitations (ECOG score 0-2), have measurable disease visible on scans, and their liver and kidneys must work well enough based on specific blood tests.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My kidneys work well enough (creatinine clearance ≥ 50 mL/min).

My liver tests are within the normal range set by the hospital.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either venetoclax plus obinutuzumab or sonrotoclax plus zanubrutinib. Venetoclax plus obinutuzumab involves intravenous administration and dose escalation over 12 cycles. Sonrotoclax plus zanubrutinib involves oral administration with dose escalation starting from Cycle 4 over 15 cycles.

48 weeks (12 cycles) for venetoclax plus obinutuzumab, 60 weeks (15 cycles) for sonrotoclax plus zanubrutinib

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including quality of life and disease progression.

Up to approximately 9 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to assess overall survival and long-term safety.

Long-term

Treatment Details

Interventions

• Obinutuzumab
• Sonrotoclax
• Venetoclax
• Zanubrutinib

Trial Overview The study aims to see which treatment works better for CLL: Sonrotoclax with Zanubrutinib or Venetoclax with Obinutuzumab. Participants will receive one of these combinations to compare their effectiveness in treating the condition.

Participant Groups

Group I: Sonrotoclax Plus Zanubrutinib Experimental Treatment 2 Interventions

Participants will receive from start of Cycle 1 a standard dose of zanubrutinib once or twice daily orally and in combination with sonrotoclax starting from Cycle 4 onwards at increasing doses until target dose is reached and continuing until end of Cycle 15 (each cycle is 28 days)

Group II: Venetoclax Plus Obinutuzumab Active Control 2 Interventions

Participants will receive obinutuzumab 100mg intravenously on Day 1 Cycle 1, followed by 900 mg on Day 2 Cycle 1 (or alternatively receive 1000 mg intravenously on Day 1), followed by 1000 mg on Days 8 and 15 of Cycle 1 and thereafter on Day 1 of Cycles 2 through 6 (each cycle is 28 days) in combination with venetoclax at increasing doses until target dose is reached from Day 22 Cycle 1 until end of Cycle 12 (each cycles is 28 days)

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

Approved in United States as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Approved in European Union as Gazyva for:

• Chronic Lymphocytic Leukemia (CLL)
• Follicular Lymphoma

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

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 phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

The study analyzed pharmacokinetics and exposure-response parameters of a 400 mg once-daily venetoclax regimen combined with obinutuzumab in 274 patients, confirming its suitability for first-line treatment of chronic lymphocytic leukemia (CLL).

No significant correlations were found between venetoclax exposure and progression-free survival or severe treatment-emergent adverse events, indicating that the treatment is both effective and safe at the studied dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Samineni, D., Gibiansky, L., Wang, B., et al.[2022]

Venetoclax, a BCL2 inhibitor, is currently approved in the U.S. for a specific group of patients with refractory chronic lymphocytic leukemia, indicating its targeted use in difficult-to-treat cases.

Recent data presented at the 2017 American Society of Hematology Annual Meeting suggests that venetoclax may be effective in broader applications, including combination therapies and as a first-line treatment for more patients with chronic lymphocytic leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax Data Prompt Rethink of CLL Therapy. [2021]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. [2020]

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

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. [2022]

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

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. [2022]

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

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. [2021]

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

Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. [2022]

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

Venetoclax Data Prompt Rethink of CLL Therapy. [2021]