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

Trial Summary

What is the purpose of this trial?

This phase I trial tests zanubrutinib in combination with sonrotoclax for treating underrepresented ethnic and racial minorities with B-cell non-Hodgkin lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Many racial and ethnic minorities face additional treatment challenges which may lead to poorer outcomes, however, there are fewer racial and ethnic minorities participating in clinical trials. Zanubrutinib, a type of tyrosine kinase inhibitor, blocks a protein called Bruton tyrosine kinase (BTK), which may help keep cancer cells from growing. Sonrotoclax works by blocking a protein called B-cell lymphoma-2 (Bcl-2). This protein helps certain types of blood cancer cells to survive and grow. When sonrotoclax blocks Bcl-2, it slows down or stops the growth of cancer cells and causes them to die. Zanubrutinib and sonrotoclax have been shown to be an effective treatment for B-cell cancers. Giving zanubrutinib in combination with sonrotoclax may be effective in treating ethnic and racial minorities with relapsed or refractory B-cell non-Hodgkin lymphoma.

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.

What data supports the effectiveness of the drug combination Zanubrutinib and 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 overall response rate. Additionally, venetoclax, a drug similar to Sonrotoclax, has demonstrated significant activity in treating chronic lymphocytic leukemia and small lymphocytic lymphoma, suggesting potential benefits when used in combination with other therapies. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and Sonrotoclax safe for humans?

Zanubrutinib has been studied in combination with other drugs like obinutuzumab and venetoclax, showing it is generally well tolerated in patients with conditions like chronic lymphocytic leukemia and follicular lymphoma. Common side effects included infections, low white blood cell counts, bruising, cough, diarrhea, and fatigue, with some patients needing dose adjustments or stopping treatment due to side effects. ^{1 2 3 6 7}

What makes the drug combination of Zanubrutinib and Sonrotoclax unique for treating Non-Hodgkin's Lymphoma?

Zanubrutinib is a next-generation drug that targets specific proteins in cancer cells, making it more selective and potentially safer than older treatments. When combined with Sonrotoclax, it may offer a novel approach by using two different mechanisms to attack the cancer, which could improve effectiveness and reduce the chance of resistance. ^{1 2 3 7 8}

Research Team

Geoffrey Shouse

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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, 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 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]

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]

References

1. England 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. [2022]

2. England 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. [2023]

3. England 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. [2023]

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

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma. [2022]

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

The expanding role of venetoclax in chronic lymphocytic leukemia and small lymphocytic lymphoma. [2023]

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

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]