Zanubrutinib for Diffuse Large B-Cell Lymphoma

Overseen By Massey IIT Research Operations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Virginia Commonwealth University

Must not be taking: CYP3A inducers, Warfarin

Disqualifiers: Brain metastasis, Cardiovascular disease, 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: 9

Duration: 18 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a single-arm, open label, non-randomized, phase 2 trial of zanubrutinib in patients with diffuse large B-cell lymphoma (DLBCL) who have an MYD88 L265P mutation, a CD79B mutation, a NOTCH1 truncation, or who are CD5+ by immunohistochemistry (IHC).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot be on strong CYP3A inducers or require ongoing treatment with warfarin. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug zanubrutinib for diffuse large B-cell lymphoma?

Zanubrutinib, a drug used to treat various B-cell cancers, has shown good results in other similar conditions like chronic lymphocytic leukemia and mantle cell lymphoma, with better safety and fewer side effects compared to similar drugs. Although its effect in diffuse large B-cell lymphoma is modest when used alone, combining it with other treatments may improve outcomes. ^{1 2 3 4 5}

Is zanubrutinib generally safe for humans?

Zanubrutinib has been studied in various conditions and is generally well tolerated, with common side effects including infections, bruising, and fatigue. Serious side effects like pneumonia and heart rhythm issues are less common, and the drug is considered to have a manageable safety profile. ^{1 6 7 8 9}

How is the drug zanubrutinib different from other treatments for diffuse large B-cell lymphoma?

Zanubrutinib is a next-generation drug that specifically targets Bruton's tyrosine kinase (BTK), which is important for the growth of certain cancer cells. It is more selective and has fewer side effects compared to similar drugs like ibrutinib, making it a potentially safer option for patients. ^{1 2 4 5 10}

Research Team

Bruce Hough, MD

Principal Investigator

Virginia Commonwealth University

Eligibility Criteria

This trial is for adults with diffuse large B-cell lymphoma (DLBCL) who have certain mutations (MYD88, CD79B, NOTCH1) or are CD5+ and have had no more than one R-CHOP treatment. They must be in good physical condition, not pregnant, willing to use birth control, and able to consent. Exclusions include severe allergies, brain metastasis, recent major surgery, heart issues below a set threshold, active infections like HIV or hepatitis B/C.

Inclusion Criteria

I am not allergic to corticosteroids or monoclonal antibodies.

I've had only one R-CHOP treatment and my next is scheduled within 24 days.

I am able to get out of my bed or chair and move around.

Exclusion Criteria

My lymphoma has specific genetic changes.

I have cancer that has spread to my brain.

I have an active autoimmune condition affecting my blood.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib plus R-CHOP chemotherapy for up to 6 cycles

18 weeks

6 cycles of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 3 months

Extended Follow-up

Participants are monitored for long-term outcomes up to 5 years

Up to 5 years

Treatment Details

Interventions

• Zanubrutinib

Trial Overview The study tests Zanubrutinib in patients with specific genetic markers of DLBCL. It's an open-label phase 2 trial meaning all participants receive the drug and there's no placebo group. The goal is to see how well Zanubrutinib works on its own without randomizing patients into different treatment groups.

Participant Groups

Group I: Investigational Agent Administration Experimental Treatment 1 Intervention

Zanubrutinib is administered as capsules for oral intake at one of the following dosages based on the discretion of the treating physician: * 160 mg (two 80-mg capsules) twice daily * 320 mg (four 80-mg capsules) once daily

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

Findings from Research

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 study of 27 patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL), the combination of zanubrutinib and salvage chemotherapy resulted in a high overall response rate of 74.1% and a complete remission rate of 33.3%, indicating significant efficacy.

The most common severe side effects were neutropenia and thrombocytopenia, but the treatment was generally manageable, suggesting that zanubrutinib plus chemotherapy could be a viable option for R/R DLBCL patients, especially those with poor responses to initial treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma. Yuan, X., Li, X., Huang, Y., 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]

Zanubrutinib is a highly selective second-generation BTK inhibitor that has shown deep and sustained remissions in patients with relapsed and refractory B-cell lymphoma, indicating its efficacy as a targeted therapy.

The drug has a favorable safety profile, making it a promising option for precision therapy in the treatment of B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Application of Zanubrutinib in B-Cell Lymphoma --Review]. Tang, X., Zou, WR., Peng, P., et al.[2022]

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, a selective BTK inhibitor, was evaluated in a pooled analysis of 779 patients across 6 studies, showing a generally well-tolerated safety profile with manageable and mostly reversible treatment-emergent adverse events (TEAEs).

Common nonhematologic TEAEs included upper respiratory tract infections (39%) and rash (27%), while serious adverse events like pneumonia (11%) and sepsis (2%) were noted, but the rates of atrial fibrillation and major hemorrhage were lower than those historically reported for another BTK inhibitor, ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies. Tam, CS., Dimopoulos, M., Garcia-Sanz, R., 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]

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, showed a high overall response rate of 94.5% in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma carrying the del(17p) mutation, indicating its efficacy in a challenging patient population.

The treatment was well tolerated, with an estimated 18-month progression-free survival rate of 88.6% and an overall survival rate of 95.1%, although some patients experienced adverse events, including neutropenia and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. Tam, CS., Robak, T., Ghia, P., et al.[2021]

In a phase 2 study involving 41 patients with relapsed or refractory non-GCB DLBCL, zanubrutinib showed a modest overall response rate of 29.3% and a complete response rate of 17.1%, indicating some effectiveness in this challenging subtype of lymphoma.

The safety profile of zanubrutinib was consistent with previous studies, with 48.8% of patients experiencing grade ≥ 3 adverse events, but no major hemorrhage or atrial fibrillation was reported, suggesting it may be a relatively safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. Yang, H., Xiang, B., Song, Y., et al.[2022]

Zanubrutinib demonstrated a high overall response rate of 95.4% in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, with treatment-naïve patients showing even better outcomes (100% response) compared to those with relapsed/refractory disease (91.0%).

The long-term follow-up indicated that earlier treatment with zanubrutinib leads to significantly longer progression-free and overall survival, while maintaining a favorable safety profile, with serious adverse events primarily being infections and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. Xu, W., Yang, S., Tam, CS., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma. [2022]

3. 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]

4. China pubmed.ncbi.nlm.nih.gov

[Clinical Application of Zanubrutinib in B-Cell Lymphoma --Review]. [2022]

5. 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]

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

Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies. [2022]

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

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

8. Italy pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

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

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma. [2022]

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

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies. [2022]