Zanubrutinib + Obinutuzumab + Sonrotoclax for CLL or SLL

(BOSon Trial)

Recruiting at 1 trial location

Overseen By Jacob Soumerai, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Warfarin, Dual antiplatelets, CYP3A inducers

Disqualifiers: Richter's transformation, Active infection, Heart failure, 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: 10-24 cycles (each cycle is 28 days)

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how well a combination of three medications—Zanubrutinib, Obinutuzumab, and Sonrotoclax—achieves undetectable levels of residual disease in individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not yet received treatment. The goal is to determine if this combination effectively reduces the signs of these blood cancers. Individuals diagnosed with CLL or SLL who have not received prior systemic treatment might be suitable candidates for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic corticosteroids before starting the study drugs. Other medications, like warfarin and dual antiplatelet therapy, are also not allowed during the trial. If you're on any of these, you'll need to stop them before participating.

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

Research has shown that patients generally tolerate the combination of sonrotoclax and zanubrutinib well. In studies, patients have taken doses of sonrotoclax up to 640 mg without major issues. This combination has also proven effective for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), indicating both safety and efficacy. Although obinutuzumab is part of the trial treatment, the primary focus is on the safety of the new combination, and evidence supports that patients tolerate it well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Zanubrutinib, Obinutuzumab, and Sonrotoclax for treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) because it introduces a novel approach to therapy. Unlike traditional treatments like chemoimmunotherapy, this regimen uses Zanubrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, which specifically targets a key protein involved in the growth of cancer cells, offering a potentially more precise attack on the disease. Sonrotoclax, a BCL-2 inhibitor, works by promoting cancer cell death, which complements the action of Zanubrutinib. This combination aims to enhance the effectiveness and possibly reduce the side effects compared to standard treatments, offering hope for improved patient outcomes.

What evidence suggests that this trial's treatments could be effective for CLL or SLL?

This trial will evaluate the combination of zanubrutinib, obinutuzumab, and sonrotoclax for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Research has shown that combining these drugs may be effective. Specifically, studies have found that using sonrotoclax and zanubrutinib together can make the cancer difficult to detect in the body. Adding obinutuzumab to the treatment helps target and destroy cancer cells. These treatments work together to reduce the amount of cancer remaining in the body after treatment. Early results suggest this combination can lead to positive outcomes for people who have not yet received treatment for CLL or SLL. ^{1 2 3 4 6}

Who Is on the Research Team?

Jacob Soumerai, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults with untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Participants must be over 18, have good organ function, and agree to use contraception. Exclusions include prior anti-CD20 therapy, active infections, certain heart conditions, inability to swallow pills, and recent live vaccines.

Inclusion Criteria

Willingness to not donate or bank sperm or oocytes during the study treatment period and after treatment discontinuation

I agree to use contraception if my partner can become pregnant.

Ability to understand and sign a written informed consent document

Exclusion Criteria

I have received anti-CD20 therapy before.

I do not have any active infections or bleeding disorders.

I have a history of HIV or active hepatitis B/C.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib, obinutuzumab, and sonrotoclax. Treatment duration is based on MRD response kinetics, with 10 cycles for those achieving ΔMRD400 and 24 cycles for those who do not.

10-24 cycles (each cycle is 28 days)

Multiple visits per cycle for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, up to 2 years after the final patient is enrolled.

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Obinutuzumab
• Sonrotoclax
• Zanubrutinib

Trial Overview

The study tests a combination of Zanubrutinib, Obinutuzumab, and Sonrotoclax in patients who haven't been treated before for CLL/SLL. It aims to see how many achieve undetectable measurable residual disease (uMRD), indicating very low levels of cancer cells.

How Is the Trial Designed?

Group I: Zanubrutinib, obinutuzumab, and sonrotoclax Experimental Treatment 3 Interventions

Zanubrutinib will be taken orally twice daily on days 1-28 of each cycle. Sonrotoclax will be taken orally once daily on days 1-28 starting cycle 3 day 1. Obinutuzumab will be given into the vein (by intravenous infusion) at the following timepoints: Days 1, 8, and 15 of cycle 1, Day 2 of cycle 1, and Day 1 of cycles 2 through 6. The total regimen treatment duration depends on early MRD response kinetics (ΔMRD400). The total regimen treatment duration will be 10 cycles for patients who achieve ΔMRD400 and 24 cycles for patients who do not achieve ΔMRD400 (including the 2-month zanubrutinib/obinutuzumab lead-in). Drug diaries will be provided to participants to document information about zanubrutinib and sonrotoclax.

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

BeOne Medicines

Industry Sponsor

BeOne Medicines

Collaborator

Published Research Related to This Trial

The combination of venetoclax and obinutuzumab has been approved as a superior first-line treatment for elderly, unfit patients with chronic lymphocytic leukaemia (CLL), showing better efficacy than chlorambucil/obinutuzumab based on a phase-III trial.

For patients with high-risk features like deletion 17p or TP53 mutations, targeted therapies such as ibrutinib or venetoclax/obinutuzumab are recommended due to their poor response to traditional chemotherapy, highlighting the importance of personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. Cramer, P., von Tresckow, J., Eichhorst, B., et al.[2021]

In a phase 1b study involving 12 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), a fixed-duration regimen combining obinutuzumab, ibrutinib, and venetoclax resulted in a high overall response rate of 92%, with 42% of patients achieving complete remission.

The treatment regimen was found to be safe and tolerable, with no clinically significant tumor lysis syndrome reported, indicating that this combination therapy could effectively induce deep responses in CLL patients and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Rogers, KA., Huang, Y., Ruppert, AS., et al.[2022]

Venetoclax, an oral BCL-2 inhibitor, combined with obinutuzumab, has demonstrated superior efficacy compared to traditional chemoimmunotherapy in both treatment-naive and relapsed/refractory chronic lymphocytic leukemia (CLL) patients.

Obinutuzumab, a novel anti-CD20 monoclonal antibody, has been safely used with other targeted therapies like venetoclax, showing better outcomes than the older drug rituximab when paired with chlorambucil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. Salvaris, R., Opat, S.[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 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]

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]

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]

Citations

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In a phase 1 study in patients with TN CLL treated with sonrotoclax + zanubrutinib, efficacy data was promising with ORR and 1-year progression- ...

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Sonrotoclax and Zanubrutinib as a Frontline CLL Treatment

The combination of sonrotoclax and zanubrutinib was well-tolerated and produced high rates of undetectable disease in patients with treatment-naïve CLL.

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Sonrotoclax Plus Zanubrutinib Is Safe, Efficacious in ...

The combination therapy showed a 97% overall response rate and a 57% complete response rate in relapsed/refractory CLL/SLL patients. · No dose- ...