Sonrotoclax + Zanubrutinib vs Venetoclax + Obinutuzumab for Chronic Lymphocytic Leukemia

Not currently recruiting at 295 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: BeOne Medicines

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which treatment is more effective for people with chronic lymphocytic leukemia (CLL), a type of blood cancer. Researchers are testing two different drug combinations: one group will receive sonrotoclax (BGB-11417) and zanubrutinib, while the other will receive venetoclax and obinutuzumab (Gazyva). The trial seeks participants who have not received prior treatment for CLL and have a confirmed diagnosis requiring treatment. Those with CLL who have not undergone any previous treatments may be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research shows that the combination of sonrotoclax and zanubrutinib is generally well-tolerated by people with chronic lymphocytic leukemia (CLL). Studies indicate that this treatment is safe, with manageable side effects. Earlier research found that all patients responded positively to some degree.

Long-term studies have confirmed the safety of the venetoclax and obinutuzumab combination for CLL patients. Many have used this treatment successfully, experiencing manageable side effects. This combination has proven effective and is considered a reliable option for CLL treatment. Both treatments are supported by strong evidence of safety, making them promising choices for those considering joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Sonrotoclax and Zanubrutinib for chronic lymphocytic leukemia (CLL) because these drugs offer a fresh approach compared to traditional treatments like Venetoclax and Obinutuzumab. Zanubrutinib is a Bruton’s tyrosine kinase inhibitor that may provide more targeted action with potentially fewer side effects, while Sonrotoclax, a BCL-2 inhibitor, is being studied for its ability to effectively induce cancer cell death. This combo could enhance treatment effectiveness and patient outcomes by providing a novel mechanism of action, possibly leading to less resistance and improved management of CLL.

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

This trial will compare two treatment options for chronic lymphocytic leukemia (CLL): Sonrotoclax plus Zanubrutinib and Venetoclax plus Obinutuzumab. Research has shown that the combination of Sonrotoclax and Zanubrutinib, which participants in this trial may receive, appears promising for treating CLL. Previous studies found high rates of MRD (minimal residual disease) clearance, indicating the treatment can reduce cancer cells to very low levels. One study reported a 100% overall response rate, meaning all patients saw their cancer shrink or disappear.

In contrast, Venetoclax plus Obinutuzumab, another treatment option in this trial, has well-established results. A long-term study showed that 53% of patients remained progression-free (their disease didn't worsen) after six years. This combination has proven superior to traditional chemoimmunotherapy, helping many patients live longer without signs of the disease. Both treatment options are effective, but they work in slightly different ways and offer different benefits. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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?

BeOne Medicines

Lead Sponsor

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1012/531224/Sonrotoclax-and-Zanubrutinib-as-Frontline

Sonrotoclax and Zanubrutinib as Frontline Treatment for CLL ... Sonrotoclax and Zanubrutinib as frontline treatment for CLL demonstrates high MRD clearance rates with good tolerability.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06637501

NCT06637501 | A Study to Investigate Sonrotoclax ... When Sonrotoclax blocks Bcl-2 it slows down or stops the growth of tumor cells and helps them die. This can lead to improvements in patients with CLL disease.

3. haematologica.org haematologica.org/article/view/12854

SONROTOCLAX AND ZANUBRUTINIB AS FRONTLINE ... CONCLUSIONS: Sonrotoclax + zanubrutinib was well tolerated in patients with TN-CLL/SLL. Substantial efficacy was observed, with 100% ORR in ...

4. beonemedinfo.com beonemedinfo.com/CongressDocuments/OpatBGB-11417-101iwCLLPoster2025.pdf

Updated Results From the Phase 1 Study of Sonrotoclax ( ... cAll MRD-evaluable set includes patients with ≥1 post-baseline MRD sample or disease progression or death prior to MRD assessment, excluding those with baseline ...

5. healthtree.org healthtree.org/cll/community/articles/ash-24-sonrotoclax-zanubrutinib-first-cll-therapy

Sonrotoclax + Zanubrutinib: First CLL Treatment This duo has shown improved effectiveness and fewer side effects compared to its first-generation counterparts, ibrutinib and venetoclax. A ...

6. conference-correspondent.com conference-correspondent.com/highlights/ash/ash-2023-cll/phase-1-2-study-data-of-combination-sonrotoclax-bgb-11417-plus-zanubrutinib-in-treatment-naive-cll-sll

Phase 1/2 Study Data of Combination Sonrotoclax (BGB- ... Data from an ongoing, first-in-human phase 1/2 study suggests that combination sonrotoclax (160 mg and 320 mg) plus zanubrutinib therapy was well tolerated ...