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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests zanubrutinib, a medication that might help treat diffuse large B-cell lymphoma (DLBCL), a type of blood cancer. Researchers focus on individuals whose DLBCL exhibits certain genetic markers or characteristics, such as specific mutations or protein markers. Participants must have a DLBCL diagnosis, measurable disease on imaging tests, and must not have received more than one cycle of the standard chemotherapy regimen known as R-CHOP. The goal is to determine if zanubrutinib can effectively treat DLBCL with these specific traits. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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.

Is there any evidence suggesting that zanubrutinib is likely to be safe for humans?

Research has shown that zanubrutinib is generally well-tolerated by patients with certain blood cancers, such as some lymphomas. Studies have found that its side effects are similar to those of other drugs in its class, known as BTK inhibitors, aligning with what doctors expect from these medications.

In earlier studies, patients taking zanubrutinib experienced lower rates of irregular heartbeats and secondary cancers compared to some other treatments. This suggests zanubrutinib might have fewer serious side effects. However, like all medications, it can still cause side effects. Participants should discuss potential risks with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for diffuse large B-cell lymphoma?

Zanubrutinib is unique because it targets the Bruton’s tyrosine kinase (BTK) in a more selective and potent manner compared to current treatments for diffuse large B-cell lymphoma, like R-CHOP or CAR T-cell therapy. Researchers are excited about Zanubrutinib because its precise targeting can potentially lead to fewer side effects and improved efficacy. Additionally, its oral administration offers a convenient alternative to intravenous therapies, potentially improving patient quality of life.

What evidence suggests that zanubrutinib might be an effective treatment for diffuse large B-cell lymphoma?

Studies have shown that zanubrutinib can help treat diffuse large B-cell lymphoma (DLBCL), especially in patients with specific genetic changes. One study found that patients with high levels of certain proteins (MYC/BCL-2) responded better to zanubrutinib, with 61% showing improvement compared to 29% of others. Another study tested zanubrutinib with R-CHOP, a common DLBCL treatment, and reported encouraging results, suggesting it could be a strong addition to the treatment plan. Zanubrutinib has also proven safe and effective for patients whose DLBCL returned or didn't respond to initial treatment. In this trial, participants will receive zanubrutinib as an investigational agent. Overall, these findings suggest that zanubrutinib could be a helpful option for some patients with DLBCL. ^{4 6 7 8 9}

Who Is on the Research Team?

Bruce Hough, MD

Principal Investigator

Virginia Commonwealth University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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 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]

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, 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]

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6517/527471/Treatment-Outcomes-of-Zanubrutinib-Based-Regimen

Treatment Outcomes of Zanubrutinib-Based Regimen in ... This study applied a regimen combining Zanubrutinib for double-expressor diffuse large B-cell lymphoma, achieving favorable outcomes and tolerability.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11936942/

Zanubrutinib plus R-CHOP improves the treatment effect of ... In a phase 1/2 clinical study, zanubrutinib demonstrated promising safety and efficacy in patients with relapsed/refractory DLBCL (27). In a ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124093182

A Multicenter Study on Front-Line Treatment of Diffuse ... The traditional treatment regimen, RCHOP, achieves a complete response (CR) rate of 75% and a 10-year overall survival (OS) rate of 43.5%.

4. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(25)02278-5/fulltext

Zanubrutinib Plus R-CHOP in Diffuse Large B-Cell ... Combined zanubrutinib and R-CHOP therapy shows promising and consistent efficacy in patients with DLBCL, warranting further validation in large-scale randomized ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2024.2343779

Zanubrutinib is effective in non-germinal-center B-cell-like ... Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, ...

6. ashpublications.org ashpublications.org/bloodadvances/article/6/4/1296/477740/Pooled-safety-analysis-of-zanubrutinib-monotherapy

Pooled safety analysis of zanubrutinib monotherapy in ... Pooled safety data from zanubrutinib monotherapy studies in B-cell malignancies are consistent with the toxicity profile of BTK inhibitors.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8864647/

Pooled safety analysis of zanubrutinib monotherapy in ... Pooled safety data from zanubrutinib monotherapy studies in B-cell malignancies are consistent with the toxicity profile of BTK inhibitors.

8. sciencedirect.com sciencedirect.com/science/article/pii/S2473952921007175

Zanubrutinib monotherapy for relapsed or refractory non- ... Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL.

9. beonemedinfo.com beonemedinfo.com/CongressDocuments/Zhu_BGB-3111_Pooled%20Safety_ESMO_Asia_Presentation_2023.pdf

Pooled Safety Analysis of Zanubrutinib Monotherapy in ... population with B-cell lymphoma in previous zanubrutinib studies. • Lower rates of atrial fibrillation/flutter and second primary ...