Zanubrutinib + Anti-CD20 for Lymphoma

(MAHOGANY Trial)

Recruiting at367 trial locations

Overseen by Study Director

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: BeiGene

Must not be taking: Corticosteroids, Lenalidomide

Disqualifiers: Aggressive lymphoma, Cardiovascular disease, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of the study is to compare the efficacy of zanubrutinib plus obinutuzumab versus lenalidomide plus rituximab (R\^2) in participants with relapsed/refractory (R/R) follicular lymphoma (FL), as measured by progression-free survival as determined by an independent review committee in accordance with the 2014 modification of the International Working Group on non-Hodgkin lymphoma (NHL) Criteria based on n positron emission tomography and computed tomography (PET/CT), and to compare the efficacy of zanubrutinib plus rituximab versus R\^2 in participants with R/R marginal zone lymphoma (MZL), as measured by progression free survival (PFS) assessed by IRC in accordance with CT-based Lugano 2014 Criteria.

Do I have to stop taking my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or have an active infection requiring treatment, you may not be eligible to participate.

What data supports the effectiveness of the drug combination Zanubrutinib + Anti-CD20 for Lymphoma?

Research shows that lenalidomide combined with rituximab, both part of the treatment, is effective in treating follicular lymphoma, especially in patients who have not responded to previous treatments. This combination has been shown to improve outcomes and is well-tolerated, making it a promising option for patients with relapsed or refractory lymphoma. ^{1 2 3 4 5}

What is the safety profile of Zanubrutinib + Anti-CD20 for Lymphoma?

Lenalidomide, when used with anti-CD20 antibodies like obinutuzumab or rituximab, has a manageable safety profile. Common side effects include neutropenia (low white blood cell count), fatigue, and skin rash, which are generally manageable with dose adjustments. Serious side effects are rare, and the treatment is generally well tolerated in patients with lymphoma. ^{1 3 6 7 8}

What makes the Zanubrutinib + Anti-CD20 drug unique for lymphoma?

This treatment combines Zanubrutinib, a targeted therapy, with anti-CD20 antibodies like Rituximab and Obinutuzumab, and Lenalidomide, an immunomodulatory drug, offering a novel approach by targeting multiple pathways in lymphoma cells. This combination aims to enhance efficacy by using different mechanisms of action, potentially improving outcomes for patients with relapsed or refractory lymphoma. ^{1 9 10 11 12}

Research Team

Study Director

Principal Investigator

BeiGene

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for adults with relapsed/refractory Follicular or Marginal Zone Lymphoma who've had at least one prior treatment including an anti-CD20 agent but didn't respond well. They must have measurable disease and good bone marrow, liver, and kidney function.

Inclusion Criteria

My bone marrow, liver, and kidneys are functioning well.

I need medication for my follicular lymphoma or marginal zone lymphoma.

You have a medical condition that can be measured by a CT scan or MRI.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either zanubrutinib plus obinutuzumab or lenalidomide plus rituximab for follicular lymphoma, and zanubrutinib plus rituximab or lenalidomide plus rituximab for marginal zone lymphoma. Following combination treatment, participants may continue with zanubrutinib monotherapy until disease progression or other criteria are met.

Follow-up

Participants are monitored for safety and effectiveness after treatment

87 months

Treatment Details

Interventions

• Lenalidomide (Immunomodulatory Agent)
• Obinutuzumab (CD20-Directed Cytolytic Antibody)
• Rituximab (CD20-Directed Cytolytic Antibody)
• Zanubrutinib (Bruton's Tyrosine Kinase (BTK) Inhibitor)

Trial Overview The study compares two treatments: Zanubrutinib plus Obinutuzumab versus Lenalidomide plus Rituximab. It measures which is better at stopping the lymphoma from progressing using PET/CT scans for Follicular Lymphoma and CT scans for Marginal Zone Lymphoma.

Participant Groups

Group I: Marginal Zone Lymphoma Arm C: Zanubrutinib plus Rituximab Experimental Treatment 2 Interventions

Participants will receive zanubrutinib and rituximab. Following the completion of the combination treatment, participants will continue receiving zanubrutinib monotherapy until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first.

Group II: Follicular Lymphoma Arm A: Zanubrutinib plus Obinutuzumab Experimental Treatment 2 Interventions

Participants will receive zanubrutinib and Obinutuzumab. Following the completion of the combination treatment, participants will continue receiving zanubrutinib monotherapy until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first.

Group III: Marginal Zone Lymphoma Arm D: Lenalidomide plus Rituximab Active Control 2 Interventions

Participants will receive lenalidomide and rituximab.

Group IV: Follicular Lymphoma Arm B: Lenalidomide plus Rituximab Active Control 2 Interventions

Participants will receive lenalidomide and rituximab.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In the phase III AUGMENT trial, lenalidomide combined with rituximab significantly improved progression-free survival in patients with relapsed or refractory follicular lymphoma compared to placebo, showing particular benefit for elderly patients.

Lenalidomide has an acceptable safety profile, although it can cause more frequent cases of severe neutropenia, which can be managed with dosage adjustments and growth factor support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. Blair, HA.[2021]

In a phase II trial involving 50 patients with indolent B-cell or mantle cell lymphomas who were previously resistant to rituximab, the combination of lenalidomide and rituximab resulted in a significant increase in overall response rate from 30.2% after lenalidomide alone to 62.8% after adding rituximab.

The median progression-free survival for patients receiving the lenalidomide-rituximab combination was 22.2 months, which was significantly longer than the 9.13 months observed with prior rituximab treatment, indicating that this combination can effectively overcome previous resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Chong, EA., Ahmadi, T., Aqui, NA., et al.[2022]

In a phase 2 study involving 89 patients with relapsed or refractory follicular lymphoma, 79% achieved an overall response after treatment with lenalidomide and obinutuzumab, demonstrating significant efficacy in this patient population.

The treatment had a manageable safety profile, with common adverse events including neutropenia and asthenia, and serious adverse events reported in 34% of patients, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. Morschhauser, F., Le Gouill, S., Feugier, P., et al.[2019]

Lenalidomide is an FDA-approved immunomodulatory drug that shows strong efficacy in treating multiple myeloma and certain B-cell malignancies, particularly when combined with monoclonal antibodies like rituximab.

The drug works by modifying the tumor microenvironment and enhancing the activity of T and natural-killer (NK) cells, demonstrating excellent tolerability and potential to change treatment approaches for non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. Arora, M., Gowda, S., Tuscano, J.[2022]

Lenalidomide, when used in combination with rituximab, has been shown to be an effective treatment for patients with relapsed or refractory follicular lymphoma, offering a chemotherapy-free option.

This combination therapy improves outcomes compared to using rituximab alone and may serve as a viable alternative to traditional chemoimmunotherapy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in follicular lymphoma. Flowers, CR., Leonard, JP., Fowler, NH.[2021]

Lenalidomide, especially when combined with rituximab (the 'R(2)' regimen), shows enhanced efficacy in treating indolent B-cell and mantle cell lymphomas, even in patients resistant to rituximab, while maintaining a manageable safety profile.

The most common serious side effect is asymptomatic neutropenia, which can be managed through dose adjustments, and while immune-related symptoms like rash are more frequent with the R(2) regimen, they are generally low-grade and manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. Ruan, J., Shah, B., Martin, P., et al.[2020]

Lenalidomide has shown significant efficacy in improving survival rates for patients with relapsed and refractory myeloma, especially when used alongside other treatments like bortezomib and thalidomide.

While lenalidomide is effective, it is associated with common side effects such as fatigue and thrombocytopenia, and its combination with other agents can increase the risk of blood clots, highlighting the importance of managing these adverse events for continued treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide for the treatment of relapsed and refractory multiple myeloma. van de Donk, NW., Görgün, G., Groen, RW., et al.[2021]

The combination of oral lenalidomide and obinutuzumab was found to be well tolerated and effective in treating relapsed or refractory follicular lymphoma, with a response rate of 63.2% among participants.

The study established a recommended dose of lenalidomide at 20 mg, as higher doses increased the risk of grade 3/4 neutropenia, although no maximum tolerated dose was reached during the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma. Morschhauser, F., Salles, G., Le Gouill, S., et al.[2021]

Lenalidomide is an effective and well-tolerated treatment for multiple myeloma and shows promise for patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma.

The review highlights the potential of lenalidomide, especially in combination with rituximab, as a therapeutic option, aiming to guide future clinical studies to enhance survival rates for these lymphoma types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. Desai, M., Newberry, KJ., Romaguera, J., et al.[2021]

The combination of lenalidomide and rituximab (LR) showed a significantly higher overall response rate (76%) compared to lenalidomide alone (53%) in patients with recurrent follicular lymphoma, indicating that LR is more effective in treating this condition.

Both treatment regimens had similar rates of severe adverse events (grade 3 to 4), but lenalidomide alone resulted in more treatment failures, suggesting that LR may provide a better balance of efficacy and tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). Leonard, JP., Jung, SH., Johnson, J., et al.[2022]

In a phase 2 trial involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib, lenalidomide, and rituximab resulted in a high overall response rate of 76%, with 56% achieving a complete response, suggesting this triplet therapy is effective.

While the treatment showed promising efficacy, it was associated with significant adverse events, including neutropenia in 38% of patients and three treatment-related deaths, highlighting the need for careful monitoring and further evaluation in randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Jerkeman, M., Eskelund, CW., Hutchings, M., et al.[2022]

Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown to induce responses in nearly 50% of patients with relapsed follicular/low-grade non-Hodgkin's lymphoma, with complete remissions occurring in 6% of cases, highlighting its efficacy in treating this type of cancer.

The drug is generally well tolerated, with common side effects being mild to moderate fevers and chills, and it is also effective against various other B-cell malignancies, suggesting its potential for broader applications in both cancer treatment and autoimmune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. Cheson, BD.[2019]

References

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

Lenalidomide: A Review in Previously Treated Follicular Lymphoma. [2021]

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

Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study. [2019]

4. England pubmed.ncbi.nlm.nih.gov

A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. [2022]

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

Lenalidomide in follicular lymphoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas. [2020]

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

Lenalidomide for the treatment of relapsed and refractory multiple myeloma. [2021]

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

An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. [2021]

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

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). [2022]

11. England pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. [2019]