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

Trial Summary

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.

What data supports the effectiveness of the drug combination Rituximab and Zanubrutinib for treating lymphoma?

Rituximab has shown significant effectiveness in treating various types of B-cell lymphomas, including non-Hodgkin's lymphoma, by targeting the CD20 antigen on cancer cells. It has been effective both as a single agent and in combination with chemotherapy, leading to better outcomes in patients with relapsed or refractory lymphomas. ^{1 2 3 4 5}

What safety information is available for Rituximab and Zanubrutinib in humans?

Rituximab, used for various conditions including lymphoma, has been associated with infusion-related reactions ranging from mild skin rashes to severe allergic reactions. It is generally well tolerated, but serious adverse events have been reported, sometimes requiring intensive care. Zanubrutinib's safety profile is not detailed in the provided research. ^{1 6 7 8 9}

What makes the drug combination of Rituximab and Zanubrutinib unique for treating lymphoma?

The combination of Rituximab and Zanubrutinib is unique because it targets B-cell lymphomas by using Rituximab to bind to the CD20 antigen on B cells, enhancing their clearance, while Zanubrutinib inhibits Bruton tyrosine kinase, reducing B-cell activity. This dual approach may offer a novel mechanism of action compared to traditional chemotherapy regimens. ^{1 3 5 10 11}

What is the purpose of this trial?

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 (marginal zone lymphoma and follicular lymphomas).

Research Team

Sameh Gaballa, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

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 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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rituximab: clinical development and future directions. [2019]

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

Use of rituximab, the new FDA-approved antibody. [2019]

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

Evolving role of rituximab in the treatment of patients with non-Hodgkin's lymphoma. [2015]

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

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

5. England 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. [2022]

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

Post-marketing safety of antineoplasic monoclonal antibodies: rituximab and trastuzumab. [2015]

7. New Zealand 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. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective. [2021]

9. England 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. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Rituximab therapy in malignant lymphoma. [2022]

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

Life-threatening disseminated enterovirus infection during combined rituximab and ibrutinib maintenance treatment for mantle cell lymphoma: a case report. [2021]