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

Trial Summary

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.

What data supports the effectiveness of the drug combination Zanubrutinib, Obinutuzumab, and Sonrotoclax for CLL or SLL?

The combination of Obinutuzumab and other similar drugs like Venetoclax has shown effectiveness in treating chronic lymphocytic leukemia (CLL), providing a chemotherapy-free option with good patient responses. Obinutuzumab, when combined with targeted therapies, has demonstrated significant clinical activity and safety in CLL treatment. ^{1 2 3 4 5}

Is the combination of Zanubrutinib, Obinutuzumab, and Sonrotoclax safe for humans?

The combination of Zanubrutinib and Obinutuzumab has been generally well tolerated in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), with common side effects including infections and neutropenia (low white blood cell count). Obinutuzumab has been safely combined with other agents like venetoclax, showing manageable side effects such as neutropenia and infections. While specific data on Sonrotoclax is not provided, the safety of similar combinations suggests a potentially acceptable safety profile. ^{1 3 5 6 7}

What makes the combination of Zanubrutinib, Obinutuzumab, and Sonrotoclax unique for treating CLL or SLL?

This treatment combines Zanubrutinib, a Bruton tyrosine kinase inhibitor, with Obinutuzumab, an anti-CD20 antibody, and Sonrotoclax, which may offer a novel mechanism of action. This combination is unique because it integrates different targeted therapies that may work together to improve outcomes for patients with CLL or SLL, potentially offering an alternative to traditional chemoimmunotherapy. ^{1 2 3 4 8}

What is the purpose of this trial?

The purpose of this study is to determine the proportion of participants who achieve undetectable measurable residual disease (uMRD) in previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Research Team

Jacob Soumerai, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

References

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

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. [2021]

3. 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]

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

Venetoclax and obinutuzumab for frontline treatment of chronic lymphocytic leukemia. [2021]

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

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. [2022]

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

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

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

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

8. 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]