Rituximab + Zanubrutinib for Lymphoma

Overseen By Richard Corona

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Warfarin, CYP3A inhibitors

Disqualifiers: Prior lymphoma therapy, CNS involvement, 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: 1

Duration: 24 months

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of two medications, rituximab (also known as Rituxan, Riabni, Ruxience, or Truxima) and zanubrutinib (also known as Brukinsa), for treating specific types of untreated B-cell lymphomas, namely marginal zone and follicular lymphomas. The trial aims to determine how well this combination stops or slows the disease. It includes two groups: one for marginal zone lymphoma and another for follicular lymphoma. Suitable participants have not yet received treatment for these specific lymphomas and require systemic therapy (treatment affecting the whole body). As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot be on warfarin, other Vitamin K antagonists, or certain CYP3A inhibitors or inducers. You should also be off corticosteroids 5 days before starting the trial.

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

Research shows that patients generally tolerate the combination of rituximab and zanubrutinib well. In previous studies, zanubrutinib effectively controlled disease, achieving a 72.9% success rate over two years for patients with hard-to-treat lymphomas. Additionally, earlier research demonstrated that zanubrutinib, when combined with another drug, was well tolerated, with most participants experiencing no serious side effects.

Rituximab is a common and safe treatment for certain lymphomas. The goal of combining these treatments is to enhance effectiveness while keeping side effects manageable. Although all treatments carry some risks, current evidence suggests that this combination is a promising and manageable option for those with untreated B-cell lymphomas. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Rituximab and Zanubrutinib for treating follicular and marginal zone lymphoma because it pairs a standard therapy with a newer, promising drug. Zanubrutinib is a Bruton's Tyrosine Kinase (BTK) inhibitor, which works differently from traditional treatments by specifically targeting and disrupting cancer cell signaling pathways. This novel action can potentially lead to more effective control of the disease with fewer side effects. Plus, Zanubrutinib is taken orally, offering a convenient alternative to some therapies that require intravenous administration. Together, this combination could offer a more effective and patient-friendly treatment option.

What evidence suggests that this trial's treatments could be effective for B-cell lymphomas?

This trial will evaluate the combination of zanubrutinib with rituximab for treating follicular lymphoma and marginal zone lymphoma. Research has shown that this combination holds promise for these conditions. Studies have found it effective and generally well-tolerated, meaning it works well against these cancers and is manageable for patients. In one study, patients with slow-growing B-cell lymphomas, including these two types, responded positively to the treatment. Another study found that after about 23 months, only 15% of patients experienced cancer progression with zanubrutinib treatment. These findings suggest that the rituximab-zanubrutinib combination could be a strong option for people with these lymphomas. ^{3 6 7 8 9}

Who Is on the Research Team?

Sameh Gaballa, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with untreated indolent B-cell lymphomas, specifically marginal zone and follicular lymphomas. Participants should meet certain health standards but specific inclusion and exclusion criteria are not provided.

Inclusion Criteria

I am a woman able to have children and have a negative pregnancy test.

My cancer cells test positive for CD20.

My cancer is classified as grade 1, 2, or 3a according to WHO standards.

Exclusion Criteria

I have been treated with a BTK inhibitor before.

I am HIV positive.

I haven't had major surgery in the last 4 weeks or minor surgery in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rituximab and zanubrutinib. Rituximab is administered for up to 6 cycles (28-day cycles), and zanubrutinib is administered daily for up to 24 cycles or until disease progression or unacceptable toxicity occurs.

24 months

Cycle 1: Days 1, 8, 15, and 22; Cycle 2-6: Day 1, every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Long-term follow-up

Participants are monitored for long-term outcomes such as progression-free survival and overall survival

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Rituximab
• Zanubrutinib

Trial Overview The study is testing the safety and effectiveness of combining two drugs: Zanubrutinib, a cancer medication, and Rituximab, an antibody therapy. The goal is to see how well they work together in treating these types of lymphoma.

How Is the Trial Designed?

Group I: Cohort B: Untreated Follicular Lymphoma Experimental Treatment 2 Interventions

Rituximab (Standard of Care) will be administered for up to 6 cycles (28-day cycles). Cycle 1: Days 1, 8, 15, and 22. Cycle 2-6: Day 1, every 28 days. Rituximab: Intravenous rituximab formulations (IV rituximab or IV rituximab biosimilars will be administered by IV infusion at a dose of 375 mg/m2 per local institutional guidelines) or subcutaneous rituximab formulations (RITUXAN HYCELA) 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously at a fixed dose per local institutional guidelines. Zanubrutinib 320 mg will be administered orally once daily starting on day 1 of cycle 1. Zanubrutinib will be continued once daily for up to 24 cycles or until disease progression or unacceptable toxicity occurs.

Group II: Cohort A: Untreated Marginal Zone Lymphoma Experimental Treatment 2 Interventions

Rituximab (Standard of Care) will be administered for up to 6 cycles (28-day cycles). Cycle 1: Days 1, 8, 15, and 22. Cycle 2-6: Day 1, every 28 days. Rituximab: Intravenous rituximab formulations (IV rituximab or IV rituximab biosimilars will be administered by IV infusion at a dose of 375 mg/m2 per local institutional guidelines) or subcutaneous rituximab formulations (RITUXAN HYCELA) 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously at a fixed dose per local institutional guidelines. Zanubrutinib 320 mg will be administered orally once daily starting on day 1 of cycle 1. Zanubrutinib will be continued once daily for up to 24 cycles or until disease progression or unacceptable toxicity occurs.

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

Approved in United States as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in European Union as MabThera for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Approved in Canada as Rituxan for:

• Non-Hodgkin's lymphoma
• Chronic lymphocytic leukemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

BeiGene, Ltd.

Collaborator

Trials

3

Recruited

1,000+

BeOne Medicines

Industry Sponsor

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

In a study of 70 multiple sclerosis patients receiving rituximab, 25.7% experienced infusion-associated reactions, primarily mild to moderate, mostly during the first infusion.

Premedication with corticosteroids significantly reduces the incidence of these reactions, and effective management strategies include using antihistamines and adjusting the infusion rate if reactions occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of infusion-associated reactions with rituximab for treating multiple sclerosis: a retrospective analysis of patients treated at a US centre. Brown, BA., Torabi, M.[2021]

In a review of 49,927 reports from the Spanish Pharmacovigilance System, rituximab was associated with common adverse reactions such as white cell disorders, hypotension, dyspnoea, and pneumonitis, with white cell disorders typically developing around 21 days after treatment.

Trastuzumab was primarily linked to cardiac failure, with many cases occurring alongside other medications, reinforcing the known safety profiles of both drugs as consistent with findings from large clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-marketing safety of antineoplasic monoclonal antibodies: rituximab and trastuzumab. González, V., Salgueiro, E., Jimeno, FJ., et al.[2015]

Rituximab significantly improves progression-free survival in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma when combined with chemotherapy, based on results from multiple randomized trials involving various treatment regimens.

The drug is generally well tolerated, with infusion reactions being the most common side effect, and it is considered cost-effective for treating certain types of lymphoma, reinforcing its status as a standard care option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on rituximab in chronic lymphocytic leukemia, low-grade or follicular lymphoma, and diffuse large B-cell lymphoma. Keating, GM.[2017]

The combination of rituximab and ibrutinib in a 57-year-old patient with mantle cell lymphoma led to a severe disseminated enterovirus infection, highlighting the significant risk of immunodeficiency and severe immune-related side effects from this treatment regimen.

High-dose intravenous immunoglobulins were effective in clearing the virus and restoring organ function, suggesting that this treatment should be considered for patients experiencing severe enterovirus infections while on rituximab and ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. Higer, M., Cana, D., Podlech, J., et al.[2021]

Rituximab is the first FDA-approved monoclonal antibody for cancer treatment, specifically targeting the CD20 antigen on B cells, and has shown efficacy in treating relapsed low-grade and follicular non-Hodgkin's lymphoma in multicenter studies.

The treatment is generally well-tolerated, with side effects mainly consisting of mild fevers and chills during the first infusion, and its low immunogenicity allows for potential future treatments without significant complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of rituximab, the new FDA-approved antibody. Leget, GA., Czuczman, MS.[2019]

In a study involving four patients with primary refractory or early relapsed T cell rich B cell lymphomas (TCRBCL), the combination of rituximab with chemotherapy (vinorelbine and gemcitabine) resulted in three complete responses and one partial response, demonstrating significant efficacy.

The treatment was well-tolerated, with no significant adverse effects reported, suggesting that rituximab combined with chemotherapy could be a promising option for treating TCRBCL and warrants further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study. Xiros, N., Economopoulos, T., Valsami, S., et al.[2022]

Rituximab is a highly effective monoclonal antibody for treating various B-cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, demonstrating a strong activity with low toxicity.

The combination of rituximab with chemotherapy (R-CHOP) has shown the highest efficacy reported for any chemotherapy regimen in treating diffuse large B-cell lymphoma and follicular lymphoma, although some patients may still be resistant to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab therapy in malignant lymphoma. Coiffier, B.[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]

Rituximab is the first monoclonal antibody approved for treating B-cell lymphomas, showing significant effectiveness in conditions like follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.

The combination of rituximab with standard chemotherapy agents (cyclophosphamide, doxorubicin, vincristine, and prednisone) has achieved the highest efficacy reported for treating diffuse large B-cell lymphoma and follicular lymphoma, while maintaining low toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. Traullé, C., Coiffier, BB.[2015]

Rituximab, a monoclonal antibody targeting CD20, is an effective biologic agent for treating B-cell malignancies and autoimmune disorders, generally well tolerated with fewer adverse events than traditional chemotherapy.

Despite its benefits, there is a growing concern about serious adverse events linked to rituximab, which can lead to complications requiring intensive care, highlighting the need for careful management and prevention strategies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective. Kasi, PM., Tawbi, HA., Oddis, CV., et al.[2021]

Rituximab, a monoclonal antibody used in treating B-cell non-Hodgkin's lymphoma, does not significantly increase the risk of most severe adverse events compared to chemotherapy alone, based on a meta-analysis of eight clinical trials.

However, there is a notable increase in the risk of fatal adverse events, particularly infections, in patients receiving rituximab, indicating a need for further investigation into its safety profile regarding infection-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin's lymphoma (B-NHL) chemotherapy: a meta-analysis. Hua, Q., Zhu, Y., Liu, H.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06350318

Rituximab and Zanubrutinib in Patients With Indolent B-cell ... The purpose of the study is to establish the safety and efficacy of zanubrutinib in combination with rituximab for people with untreated B-cell lymphomas ( ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10076791/

Zanubrutinib for the treatment of lymphoid malignancies Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the ...

3. tandfonline.com tandfonline.com/doi/full/10.2217/fon-2020-0794

A Phase III Study of Zanubrutinib Plus Rituximab Versus ... Zanubrutinib in combination with rituximab has the potential to further improve outcomes with a chemotherapy-free approach in patients with previously untreated ...

4. targetedonc.com targetedonc.com/view/five-year-follow-up-confirms-zanubrutinib-as-a-frontline-option-in-cll-sll

Five-Year Follow-Up: Zanubrutinib Frontline CLL/SLL Option The 54- and 60-month PFS rates were 80.1% and 75.8% with zanubrutinib vs 44.6% and 40.1% with BR, respectively. Additionally, the degree of PFS ...

5. 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 to obinutuzumab produced superior clinical activity, prolonged survival, and had a favorable toxicity profile compared with ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10679804/

Safety and efficacy of zanubrutinib in relapsed/refractory ... With longer follow-up, zanubrutinib showed durable disease control (2-year DOR rate of 72.9%) in patients with R/R MZL.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9198905/

Zanubrutinib monotherapy in relapsed/refractory indolent ... Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable ...

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. youtube.com youtube.com/watch?v=rBnivgRCCy0

MAGNOLIA: zanubrutinib in patients with R/R marginal zone ... This really presents itself as a safe effective and tolerable treatment for patients with modular Zone lymphoma.