Zanubrutinib + Rituximab for Chronic Lymphocytic Leukemia

Overseen By Jan A Burger, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Warfarin, Kinase inhibitors

Disqualifiers: Pregnancy, Severe heart 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: 64

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well zanubrutinib and rituximab work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma for which the patient has not received treatment in the past (previously untreated). Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. The study is being done to find out if zanubrutinib combined with rituximab can help control previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently on warfarin (Coumadin) or any other vitamin K antagonist, unless you switch to a non-vitamin K antagonist like a NOAC/DOAC at least 7 days before starting the study. Please consult with the trial team for more details.

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. However, you cannot participate if you are currently on warfarin (a blood thinner) and must switch to a different type of blood thinner at least 7 days before starting the study. It's best to discuss your specific medications with the trial team.

What data supports the idea that Zanubrutinib + Rituximab for Chronic Lymphocytic Leukemia is an effective drug?

The available research shows that Rituximab, when combined with other drugs like fludarabine and cyclophosphamide, improves survival rates for patients with Chronic Lymphocytic Leukemia (CLL). Although specific data on Zanubrutinib combined with Rituximab is not provided, Rituximab's effectiveness in combination with other treatments suggests it could be beneficial. Rituximab has been shown to increase the time patients live without the disease getting worse and overall survival when used with other chemotherapy drugs. This suggests that combining Rituximab with Zanubrutinib might also be effective, given Rituximab's proven track record in improving outcomes in CLL. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Zanubrutinib and Rituximab for treating Chronic Lymphocytic Leukemia?

Rituximab, when combined with chemotherapy, has been shown to improve survival rates in patients with Chronic Lymphocytic Leukemia. Studies have demonstrated that adding Rituximab to treatments like fludarabine and cyclophosphamide increases progression-free and overall survival compared to chemotherapy alone. ^{1 2 3 4 5}

What safety data is available for Zanubrutinib and Rituximab in treating CLL?

Zanubrutinib, a selective Bruton tyrosine kinase inhibitor, has been studied in combination with Rituximab for treating chronic lymphocytic leukemia (CLL). In the SEQUOIA trial, Zanubrutinib showed improved progression-free survival compared to bendamustine plus Rituximab. Common adverse events included upper respiratory tract infections, neutropenia, contusion, cough, diarrhea, and fatigue. Grade 3/4 adverse events were primarily neutropenia and pneumonia. Zanubrutinib was generally well tolerated, with some patients requiring dose adjustments or discontinuation due to adverse events. ^{6 7 8 9 10}

Is the combination of Zanubrutinib and Rituximab safe for humans?

Zanubrutinib, when used in combination with other treatments like obinutuzumab, has been generally well tolerated in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Common side effects include infections, bruising, fatigue, and diarrhea, with more serious effects like low white blood cell counts and pneumonia occurring less frequently. ^{6 7 8 9 10}

Is the drug Rituximab, Zanubrutinib a promising treatment for Chronic Lymphocytic Leukemia?

Yes, Rituximab, Zanubrutinib is a promising treatment for Chronic Lymphocytic Leukemia. Studies show that it significantly improves progression-free survival, meaning patients can live longer without the disease getting worse. It also has a better safety profile compared to some older treatments, making it a preferred option for many patients. ^{6 7 8 11 12}

What makes the drug Zanubrutinib + Rituximab unique for treating chronic lymphocytic leukemia?

Zanubrutinib is a next-generation drug that targets Bruton's tyrosine kinase more selectively, leading to fewer side effects compared to older treatments like ibrutinib. When combined with Rituximab, it has shown improved progression-free survival and a better safety profile, making it a promising option for patients with chronic lymphocytic leukemia. ^{6 7 8 11 12}

Research Team

Jan A. Burger

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma, who are generally healthy and not pregnant. They should be able to perform daily activities with ease to moderate difficulty (ECOG 0-2), have normal liver and kidney function tests, and no recent history of other cancers except certain skin cancers or localized cancer that has been treated.

Inclusion Criteria

I can take care of myself and am up and about more than half of the day.

I have been diagnosed with CLL/SLL and have not received any treatment.

My kidneys work well enough, with a creatinine clearance over 30 mL/min.

Exclusion Criteria

I am currently pregnant or breastfeeding.

My blood tests show very low white blood cells or platelets.

I have had minor surgery or a biopsy within the last week, but bone marrow procedures are okay.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Frontline Therapy

Patients receive zanubrutinib orally twice daily and rituximab intravenously. Treatment repeats every 28 days for up to 6 cycles.

24 weeks

4 visits (in-person) in cycle 1, 1 visit (in-person) in subsequent cycles

Extended Treatment

Patients with complete response continue zanubrutinib for up to 18 additional cycles. Patients with partial response or stable disease continue zanubrutinib and rituximab for up to 12 additional cycles.

48-72 weeks

Re-treatment for Relapsed Disease

Patients with disease relapse may restart zanubrutinib and rituximab. Treatment repeats every 28 days for up to 6 cycles, followed by zanubrutinib for up to 18 additional cycles.

48-72 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 5 years

Follow-up at 60 days, then every 120 days

Treatment Details

Interventions

• Rituximab
• Zanubrutinib

Trial Overview The trial is testing the combination of zanubrutinib, an enzyme blocker, and rituximab, a monoclonal antibody against previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. The goal is to see if this drug combo can control these blood cancers effectively.

Participant Groups

Group I: Treatment (zanubrutinib, rituximab) Experimental Treatment 2 Interventions

See Detailed Description.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Rituximab, when combined with fludarabine and cyclophosphamide, significantly improves both progression-free and overall survival in previously untreated chronic lymphocytic leukemia patients with good performance status, establishing it as the standard treatment for this group.

For patients with significant comorbidities, the combination of obinutuzumab and chlorambucil has been shown to prolong overall survival compared to chlorambucil alone, making it the standard regimen for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Monoclonal Antibodies in the Treatment of Chronic Lymphocytic Leukemia in 2015]. Obrtlíková, P., Urbanová, R.[2019]

Adding rituximab to fludarabine and cyclophosphamide (R-FC) significantly improves progression-free survival in chronic lymphocytic leukaemia (CLL) patients, with overall survival benefits noted in previously untreated patients from the CLL-8 trial.

The economic model indicates that rituximab is cost-effective in the Australian healthcare system, providing an incremental gain of 0.94 quality-adjusted life-years (QALYs) at a cost of A$42,906 per QALY gained, which is considered acceptable for healthcare interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modelling the cost effectiveness of rituximab in chronic lymphocytic leukaemia in first-line therapy and following relapse. Adena, M., Houltram, J., Mulligan, SP., et al.[2021]

Rituximab, a monoclonal antibody targeting CD20 on B lymphocytes, shows limited effectiveness as a standalone treatment for chronic lymphocytic leukemia (CLL), as it does not eliminate leukemia from the bone marrow.

However, when combined with chemotherapy, specifically fludarabine monophosphate and cyclophosphamide, rituximab significantly improves patient survival compared to chemotherapy alone, leading to its FDA approval for treating CD20-positive CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in chronic lymphocytic leukemia. James, DF., Kipps, TJ.[2023]

In a long-term follow-up study of 104 patients with chronic lymphocytic leukemia (CLL) treated with fludarabine plus rituximab, the median overall survival was 85 months, with 71% of patients alive at 5 years, indicating effective long-term outcomes.

The treatment showed a low risk of therapy-related myeloid neoplasm (t-MN), with no patients developing t-MN before relapse, supporting the safety of fludarabine plus rituximab as a first-line treatment for symptomatic CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. Woyach, JA., Ruppert, AS., Heerema, NA., et al.[2021]

Rituximab has been shown to significantly improve progression-free and overall survival in patients with various types of non-Hodgkin lymphoma and chronic lymphocytic leukaemia (CLL), based on a systematic review of 56 randomized controlled trials.

The consensus guidelines recommend rituximab for use in combination with chemotherapy for initial treatment of aggressive B-cell lymphomas, maintenance therapy for indolent B-cell lymphomas, and as part of treatment regimens for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. Prica, A., Baldassarre, F., Hicks, LK., et al.[2018]

In the phase 3 SEQUOIA trial involving adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), zanubrutinib significantly improved progression-free survival compared to the standard treatment of bendamustine plus rituximab (BR).

Patients treated with zanubrutinib reported better health-related quality-of-life outcomes at 12 and 24 weeks, including improvements in global health status, physical functioning, and reduced symptoms of diarrhea, fatigue, and nausea/vomiting compared to those receiving BR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Ghia, P., Barnes, G., Yang, K., et al.[2023]

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, 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]

Acalabrutinib, a Bruton's tyrosine kinase inhibitor, has been shown to be effective and safe for treating chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with significant improvements in efficacy observed in both monotherapy and combination treatments.

In clinical studies, acalabrutinib demonstrated a high rate of molecular remission when combined with venetoclax, while maintaining an acceptable safety profile, although some adverse events occurred in over 20% of patients, including myelosuppression and gastrointestinal issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. Egyed, M., Lueff, S., Borbely, J., et al.[2022]

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 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]

Zanubrutinib (zanu) has been shown to significantly improve progression-free survival compared to bendamustine-rituximab in treatment-naive patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as a first-line treatment option.

In a direct comparison with ibrutinib, zanu demonstrated a better safety profile and enhanced clinical efficacy, leading to its approval by the FDA and EMA as a preferred treatment for CLL/SLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. Molica, S., Tam, C., Allsup, D., et al.[2023]

References

1. Czech Republic pubmed.ncbi.nlm.nih.gov

[Monoclonal Antibodies in the Treatment of Chronic Lymphocytic Leukemia in 2015]. [2019]

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

Modelling the cost effectiveness of rituximab in chronic lymphocytic leukaemia in first-line therapy and following relapse. [2021]

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

Rituximab in chronic lymphocytic leukemia. [2023]

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

Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline. [2018]

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

Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. [2023]

7. England 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. [2023]

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

Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. [2021]

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

Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia. [2022]

10. Italy pubmed.ncbi.nlm.nih.gov

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion. [2021]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option. [2023]