Zanubrutinib + Sonrotoclax for Non-Hodgkin's Lymphoma

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Strong CYP3A inducers, Warfarin

Disqualifiers: Major surgery, Active GVHD, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to 28 cycles (28 days each)

37 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment option for certain types of blood cancers known as B-cell non-Hodgkin lymphoma, which have not responded to previous treatments or have returned after improvement. The study tests two drugs: zanubrutinib, which stops cancer cells from growing, and sonrotoclax, which makes cancer cells die. The trial aims to determine if combining these drugs can help people from underrepresented racial and ethnic groups who face unique treatment challenges. It seeks participants diagnosed with a specific type of B-cell non-Hodgkin lymphoma that requires further treatment, particularly from racial or ethnic minority groups. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop certain medications before starting the study drugs. Specifically, you must not have taken any biologic or immunologic-based therapies within 28 days, systemic chemotherapy or radiation therapy within 14 days, corticosteroids with antineoplastic intent within 7 days, or BTK inhibitors within 5 half-lives before the first dose of the study drug. Additionally, ongoing treatment with strong CYP3A inducers or warfarin is not allowed.

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

Research shows that the combination of zanubrutinib and sonrotoclax is generally well-tolerated by patients with recurring or hard-to-treat blood cancers. In studies with patients who have similar conditions, this treatment has proven effective and manageable. The safety profile is considered acceptable, with side effects that are not severe and can be managed. These findings suggest a positive outlook for safety, though it's important to note that they are based on early trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Zanubrutinib combined with Sonrotoclax for treating Non-Hodgkin's Lymphoma because it uses a novel mechanism of action. While standard treatments often involve chemotherapy or monoclonal antibodies targeting the cancer cells directly, Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that disrupts pathways crucial for cancer cell survival and proliferation. Sonrotoclax, on the other hand, is a BCL-2 inhibitor, which helps in promoting cancer cell death by targeting proteins that prevent apoptosis. Together, these drugs offer a two-pronged attack on the cancer cells, potentially leading to more effective outcomes with a novel approach compared to existing therapies.

What evidence suggests that zanubrutinib and sonrotoclax might be an effective treatment for non-Hodgkin's lymphoma?

Studies have shown that using zanubrutinib and sonrotoclax together can be effective for certain types of B-cell non-Hodgkin lymphoma. Specifically, this combination led to a 79% overall response rate and a 66% complete response rate in patients with mantle cell lymphoma that returned or did not respond to other treatments. In this trial, participants will receive zanubrutinib and sonrotoclax as part of the treatment regimen. Zanubrutinib blocks a protein that aids cancer cell growth, while sonrotoclax targets a protein that helps cancer cells survive. This combination can both stop cancer cells from growing and help kill them. These results are promising, especially for those whose cancer has returned or not responded to other treatments. ^{1 4 5 6 7}

Who Is on the Research Team?

Geoffrey Shouse

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for underrepresented ethnic and racial minorities with B-cell non-Hodgkin lymphoma that has either relapsed or is refractory. Specific eligibility criteria are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

Assent, when appropriate, will be obtained per institutional guidelines

I can do most of my daily activities on my own.

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I have not received a live vaccine within 35 days before starting the study drug.

I have not had major surgery within the last 4 weeks.

I have been treated with a Bcl2 inhibitor for at least 2 months or my condition worsened on it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib orally once daily on days 1-28 of each cycle. Starting with cycle 3, participants also receive sonrotoclax orally once daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 28 cycles.

Up to 28 cycles (28 days each)

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days then every 3 months for up to 3 years.

Up to 3 years

Follow-up visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Sonrotoclax
• Zanubrutinib

Trial Overview The trial tests zanubrutinib combined with sonrotoclax in patients. Zanubrutinib targets a protein to stop cancer growth; sonrotoclax blocks another protein to kill cancer cells. The study aims to see if this combination works well in the specified patient group.

How Is the Trial Designed?

Group I: Treatment (zanubrutinib, sonrotoclax) Experimental Treatment 9 Interventions

Patients receive zanubrutinib PO QD on days 1-28 of each cycle. Starting with cycle 3, patients also receive sonrotoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 28 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo urine and blood sample collection, and CT or MRI throughout the study. Additionally, patients may undergo biopsy at progression and bone marrow aspiration and biopsy throughout the study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In a phase 2 trial involving 39 patients with treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, the combination therapy of zanubrutinib, obinutuzumab, and venetoclax (BOVen) achieved an impressive 89% rate of undetectable minimal residual disease (MRD) in both blood and bone marrow after a median treatment duration of 10 months.

The BOVen regimen was well tolerated, with the most common side effects being thrombocytopenia and neutropenia, and it supports the idea of using MRD as a biomarker to guide treatment duration, potentially allowing for earlier therapy discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Soumerai, JD., Mato, AR., Dogan, A., et al.[2022]

In a study of 53 patients with relapsed/refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL), the selective Bruton's tyrosine kinase inhibitor zanubrutinib showed an overall response rate of 80% for MZL and 36.4% for FL, indicating significant efficacy in these difficult-to-treat cancers.

Zanubrutinib was generally well tolerated, with most adverse events being mild (≤ grade 2), and no reports of atrial fibrillation/flutter, suggesting a favorable safety profile for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. Phillips, T., Chan, H., Tam, CS., et al.[2022]

Zanubrutinib has been approved for treating various lymphoproliferative disorders, providing a significant option for patients who have not responded to standard therapies.

A panel of experts identified unmet clinical needs in the use of zanubrutinib for specific lymphomas, such as Waldenström macroglobulinemia, and made recommendations for future studies to optimize its use, especially for less experienced healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmet clinical needs in the use of zanubrutinib in malignant lymphomas (Waldenström macroglobulinemia, marginal zone lymphoma and mantle cell lymphoma): A consensus-based position paper from an ad hoc expert panel. Zinzani, PL., Mauro, FR., Tedeschi, A., et al.[2023]

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]

Zanubrutinib is a next-generation BTK inhibitor that shows improved selectivity and reduced off-target toxicities compared to ibrutinib, making it a safer option for treating B-cell malignancies.

In recent clinical trials, zanubrutinib demonstrated significant efficacy in improving progression-free survival in patients with chronic lymphocytic leukemia (CLL) and showed better safety profiles, including a lower risk of serious side effects like atrial fibrillation and major bleeding compared to ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. Wolska-Washer, A., Robak, T.[2023]

In a phase II study involving 217 patients with relapsed/refractory follicular lymphoma, the combination of zanubrutinib and obinutuzumab (ZO) showed a significantly higher overall response rate (ORR) of 69% compared to 46% for obinutuzumab alone, indicating greater efficacy.

The safety profile of ZO was manageable, with common side effects including thrombocytopenia and neutropenia, and serious adverse events like atrial fibrillation occurring in only 3% of patients, suggesting that ZO could be a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. Zinzani, PL., Mayer, J., Flowers, CR., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06859008

Study Details | NCT06859008 | Zanubrutinib in ... Giving zanubrutinib in combination with sonrotoclax may be effective in treating ethnic and racial minorities with relapsed or refractory B-cell non-Hodgkin ...

2. onclive.com onclive.com/view/sonrotoclax-plus-zanubrutinib-generates-durable-responses-in-r-r-mantle-cell-lymphoma

Sonrotoclax Plus Zanubrutinib Generates Durable ... Sonrotoclax combined with zanubrutinib achieved a 79% ORR and 66% CR rate in patients with relapsed/refractory MCL. No dose-limiting toxicities ...

3. ajmc.com ajmc.com/view/positive-topline-results-seen-for-sonrotoclax-in-r-r-mantle-cell-lymphoma

Positive Topline Results Seen for Sonrotoclax in R/R ... Sonrotoclax showed significant efficacy in relapsed or refractory mantle cell lymphoma, achieving a high overall response rate and manageable ...

4. withpower.com withpower.com/trial/zanubrutinib-sonrotoclax-for-non-hodgkins-lymphoma-f96df

Zanubrutinib + Sonrotoclax for Non-Hodgkin's Lymphoma Zanubrutinib has shown effectiveness in treating certain types of non-Hodgkin's lymphoma, such as marginal zone lymphoma and follicular lymphoma, with a high ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/hon.70093_OT03

OT03 | BGB‐11417‐302, A PHASE 3, RANDOMIZED ... Here, an ongoing phase 3 study that will compare the efficacy and safety of sonrotoclax + zanubrutinib versus sonrotoclax-matched placebo + ...

6. onclive.com onclive.com/view/updated-results-from-the-phase-1-study-of-sonrotoclax-bgb-11417-a-novel-bcl2-inhibitor-in-combination-with-zanubrutinib-for-relapsed-refractory-cll-sll-demonstrate-deep-and-durable-responses

Updated Results From the Phase 1 Study of Sonrotoclax ... The longer follow-up data demonstrate the safety and efficacy of the sonrotoclax plus zanubrutinib combination in patients with relapsed or refractory chronic ...

7. library.ehaweb.org library.ehaweb.org/eha/2025/eha2025-congress/4159236/chan.y.cheah.updated.results.from.the.phase.1.study.of.sonrotoclax.28bgb-1141729.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D2%2Atopic%3D1574%2Asearch%3Dcll

UPDATED RESULTS FROM THE PHASE 1 STUDY OF ... Results: As of December 6, 2024, 47 pts with R/R CLL/SLL were enrolled and had received combination tx (sonrotoclax doses: 40mg, n=4; 80mg, n=9; ...