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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, zanubrutinib and rituximab, to evaluate their effectiveness against chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Zanubrutinib blocks certain enzymes that promote cancer cell growth, while rituximab is an antibody designed to slow or stop the spread of cancer cells. The trial is open to individuals diagnosed with CLL or SLL who have not yet received treatment for these conditions. Participants should have health issues indicating a need for treatment, as defined by specific medical guidelines. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research shows that the combination of zanubrutinib and rituximab is generally safe for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Studies have found that most patients taking this combination experienced positive safety outcomes. For example, one study found that most patients remained in remission for 24 months without major safety issues.

When combined with rituximab, zanubrutinib has been compared to other treatments, and reports suggest it is a safe option. While some side effects can occur, they are usually manageable. Patients considering joining a trial should discuss potential risks and side effects with their healthcare providers to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for chronic lymphocytic leukemia?

Researchers are excited about zanubrutinib combined with rituximab for treating Chronic Lymphocytic Leukemia (CLL) because it offers a fresh approach compared to standard treatments like chemotherapy or other BTK inhibitors such as ibrutinib. Zanubrutinib is a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, designed to target cancer cells more precisely and potentially cause fewer side effects. When paired with rituximab, an antibody that helps the immune system mark cancer cells for destruction, this combination could offer a powerful, targeted attack on CLL. This targeted mechanism gives hope for more effective treatment outcomes and improved quality of life for patients.

What evidence suggests that zanubrutinib and rituximab might be effective for chronic lymphocytic leukemia?

Research has shown that the combination of zanubrutinib and rituximab, which participants in this trial will receive, effectively treats chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in patients who have not previously received treatment. Studies have found that this combination helps patients live longer without their cancer worsening, compared to some other treatments. Specifically, zanubrutinib has demonstrated better results than the combination of bendamustine and rituximab, another common treatment for these conditions. Additionally, the safety of this combination is considered acceptable. This suggests that using zanubrutinib and rituximab together could be a promising option for patients newly diagnosed with CLL or SLL. ^{1 3 6 7 8}

Who Is on the Research Team?

Jan A. Burger

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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, 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]

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 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]

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]

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]

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 (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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02265

Median 5-Year Follow-Up of SEQUOIA Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39289059/

Cost-Effectiveness of Zanubrutinib Versus Bendamustine ... Here, we compared the cost-effectiveness of zanubrutinib with bendamustine-rituximab (R-bendamustine) to determine its effectiveness as the ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35810754/

Zanubrutinib versus bendamustine and rituximab in ... Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03336333

NCT03336333 | A Study Comparing Zanubrutinib With ... Study Overview. Brief Summary. To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as ...

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

Five-Year Follow-Up Confirms Zanubrutinib as a Frontline ... Zanubrutinib demonstrated sustained progression-free survival vs bendamustine/rituximab at 5 years in treatment-naive chronic lymphocytic leukemia/small ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39647999/

Median 5-Year Follow-Up of SEQUOIA At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for ...

7. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3249/532346/Sustained-Superiority-of-Zanubrutinib-vs

Sustained Superiority of Zanubrutinib vs Bendamustine + ... Sustained Superiority of Zanubrutinib vs Bendamustine + Rituximab in Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma ...

8. onclive.com onclive.com/view/time-limited-zanubrutinib-rituximab-yields-durable-remissions-in-treatment-naive-cll

Time-Limited Zanubrutinib/Rituximab Yields Durable ... Zanubrutinib and rituximab therapy in CLL patients shows safety and durable remissions, with most patients remaining in remission at 24 months ...