Zanubrutinib + Anti-CD20 for Lymphoma

(MAHOGANY Trial)

Recruiting at 459 trial locations

Overseen By Study Director BeiGene

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: BeiGene

Must not be taking: Corticosteroids, Lenalidomide

Disqualifiers: Aggressive lymphoma, Cardiovascular disease, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

780 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for people with follicular lymphoma (FL) and marginal zone lymphoma (MZL) that have returned or didn't respond to previous treatments. It compares two combinations: zanubrutinib (a Bruton tyrosine kinase inhibitor) with obinutuzumab or rituximab, and lenalidomide with rituximab, to determine which better prevents cancer progression. Eligible participants must have either FL or MZL, have undergone prior treatment but require further therapy, and have cancer visible on scans. As a Phase 3 trial, this study represents the final step before FDA approval, providing patients an opportunity to access potentially effective treatments early.

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.

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

Research has shown that the combination of zanubrutinib and obinutuzumab is generally well tolerated. In one study, patients reported improved ability to perform daily activities and experienced less fatigue and nausea compared to those who only received obinutuzumab. Additionally, this combination had a manageable safety profile for patients with untreated mantle cell lymphoma, with side effects usually mild and effectively managed.

For the combination of zanubrutinib and rituximab, studies have also shown promising safety results. One study found that this combination effectively controlled marginal zone lymphoma for a significant period, with 72.9% of patients experiencing a positive response lasting at least two years, without severe side effects.

These findings suggest that both combinations have been tested with positive safety outcomes. However, always discuss potential risks and benefits with a healthcare provider before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer novel combinations targeting lymphoma. Zanubrutinib works by inhibiting Bruton's tyrosine kinase (BTK), which is crucial for cancer cell survival, and when combined with Obinutuzumab or Rituximab, it enhances the immune system's ability to attack cancer cells. Unlike traditional treatments that might rely solely on chemotherapy, these combinations aim to provide a more targeted approach with potentially fewer side effects. The use of BTK inhibitors like Zanubrutinib, alongside established monoclonal antibodies, represents a promising step in potentially improving outcomes for patients with follicular and marginal zone lymphoma.

What evidence suggests that this trial's treatments could be effective for lymphoma?

Studies have shown that zanubrutinib combined with obinutuzumab effectively treats follicular lymphoma. One study found that 69% of patients experienced a decrease in cancer signs after 20 months. Long-term results also indicated better survival rates and positive responses with this combination. In this trial, participants in the Follicular Lymphoma Arm A will receive zanubrutinib and obinutuzumab.

Research on zanubrutinib with rituximab has shown promising outcomes for marginal zone lymphoma. Specifically, one study found that 88% of patients responded well, with many experiencing full or partial remission. Participants in the Marginal Zone Lymphoma Arm C of this trial will receive zanubrutinib and rituximab. These findings suggest that both combinations could effectively treat follicular and marginal zone lymphomas that have returned or are difficult to treat. ^{4 6 7 8 9}

Who Is on the Research Team?

Study Director

Principal Investigator

BeiGene

Study Director

Principal Investigator

BeiGene

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Lenalidomide
• Obinutuzumab
• Rituximab
• Zanubrutinib

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.

How Is the Trial Designed?

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.

Lenalidomide is already approved in European Union, United States for the following indications:

Approved in European Union as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Approved in United States as Revlimid for:

• Multiple myeloma
• Myelodysplastic syndromes
• Mantle cell lymphoma
• Follicular lymphoma
• Marginal zone lymphoma

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

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]

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 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]

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]

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 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]

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 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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37506346/

A Phase II Randomized Study of Zanubrutinib Plus ... Purpose: The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib ...

2. healthtree.org healthtree.org/follicular-lymphoma/community/articles/follicular-lymphoma-zanubrutinib-obinutuzumab

Follicular Lymphoma: Zanubrutinib & Obinutuzumab Treatment outcomes. Zanubrutinib and obinutuzumab group: After 20 months of treatment, 69% of the patients achieved a reduction of cancer signs ...

3. onclive.com onclive.com/view/long-term-rosewood-data-confirm-efficacy-of-zanubrutinib-plus-obinutuzumab-in-r-r-follicular-lymphoma

Long-Term ROSEWOOD Data Confirm Efficacy of ... The addition of zanubrutinib (Brukinsa) to obinutuzumab (Gazyva) produced superior clinical activity, prolonged survival, and had a favorable ...

4. cancernetwork.com cancernetwork.com/view/zanubrutinib-combo-improves-orr-vs-obinutuzumab-in-follicular-lymphoma

Zanubrutinib Combo Improves ORR Vs Obinutuzumab in ... Combining zanubrutinib (Brukinsa) with obinutuzumab (Gazyva) improved responses, produced meaningful clinical activity, and safety compared ...

5. targetedonc.com targetedonc.com/view/fda-approves-zanubrutinib-and-obinutuzumab-in-r-r-follicular-lymphoma

FDA Approves Zanubrutinib and Obinutuzumab in R/R ... The ORR for 29 patients who crossed over to zanubrutinib plus obinutuzumab was 24.1%. The median time to next anti-lymphoma treatment was NE in ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39376156/

results from the ROSEWOOD trial Patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm.

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1630/531704/The-Efficacy-and-Safety-of-Obinutuzumab-with

The Efficacy and Safety of Obinutuzumab with Zanubrutinib As ... Obinutuzumab plus zanubrutinib demonstrated a favorable efficacy and a manageable safety profile in elderly patients with untreated MCL.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00775

ROSEWOOD: A Phase II Randomized Study of ... The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib study.

9. memoinoncology.com memoinoncology.com/follicular-lymphoma-efficacy-and-safety-updates/

Follicular lymphoma: Efficacy and safety updates The median duration of response (DOR) was 5.8 months (95 % CI: 1.5–not reached), median progression-free survival (PFS) was 5.5 months (95 % CI: 2.8–not reached) ...