Zanubrutinib vs Bendamustine + Rituximab for Chronic Lymphocytic Leukemia

(SEQUOIA Trial)

Not currently recruiting at 322 trial locations

Overseen By BeiGene

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: BeiGene

Must not be taking: Corticosteroids, CYP3A inhibitors

Disqualifiers: Cardiovascular disease, Prior malignancy, 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

Duration: Up to 27 cycles (each cycle is 28 days)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different treatments for individuals with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have not received prior treatment. Researchers compare the effectiveness of zanubrutinib, a targeted therapy, against a combination of bendamustine and rituximab in preventing disease progression. Participants will receive either zanubrutinib alone, bendamustine plus rituximab, or zanubrutinib with venetoclax. This trial may suit those diagnosed with CLL or SLL who require treatment but cannot undergo standard chemoimmunotherapy. As a Phase 3 trial, it represents the final step before FDA approval, offering access to potentially groundbreaking treatments.

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 it does mention that you cannot participate if you require ongoing treatment with strong CYP3A inhibitors or inducers (types of drugs that affect how your body processes certain medications). It's best to discuss your current medications with the trial team.

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

Previous studies have shown zanubrutinib to be generally safe. Research suggests it is easier on the heart compared to ibrutinib, with fewer heart-related side effects. In real-world use, patients taking zanubrutinib experienced fewer heart problems.

For the combination of venetoclax and zanubrutinib, research indicates it is safe and promising. Most patients responded well without serious side effects, even those with certain genetic mutations.

The combination of bendamustine and rituximab is also considered safe for initial treatment of chronic lymphocytic leukemia (CLL). It works well and is generally tolerated by patients, although those with a specific type of CLL may have a slightly shorter time without disease progression.

Overall, these treatments have been tested in people and have shown positive safety results. However, individual experiences can differ, so discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about zanubrutinib for treating chronic lymphocytic leukemia (CLL) because it works differently than traditional treatments like Bendamustine + Rituximab. While standard care often attacks cancer cells broadly, zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor, which specifically targets and blocks a protein crucial for the growth and survival of CLL cells. This targeted approach might offer a more effective and potentially less toxic option for patients. Moreover, it allows for continuous daily dosing, which could lead to more sustained control of the disease with possibly fewer side effects compared to conventional chemotherapy regimens.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

This trial will compare different treatment options for chronic lymphocytic leukemia (CLL). Research has shown that zanubrutinib, which participants in this trial may receive, effectively treats CLL and small lymphocytic lymphoma (SLL). Long-term results indicate that 72.2% of patients with certain genetic deletions did not experience disease progression after five years, and 97.3% of patients responded positively to the treatment.

Another treatment option in this trial is the combination of bendamustine and rituximab, which is also effective, particularly for patients whose CLL has returned or is difficult to treat. Clinical trials have demonstrated that this combination is a strong option for these cases.

Additionally, this trial includes a treatment arm using zanubrutinib with venetoclax, which has shown impressive results. Studies report a 95% response rate in CLL patients, leading to deep and lasting improvements, even in those with challenging genetic conditions. ^{1 6 7 8 9}

Who Is on the Research Team?

Study Director

Principal Investigator

BeiGene

Are You a Good Fit for This Trial?

This trial is for adults with previously untreated CLL or SLL who can't have standard chemoimmunotherapy. They should be relatively healthy (ECOG 0-2), expect to live at least 6 more months, and have good organ function. People with prior CLL/SLL treatment, ongoing infections, certain heart diseases, recent major surgery, pregnancy, drug addiction or other serious health issues cannot join.

Inclusion Criteria

My bone marrow is working well.

Measurable disease by imaging

My kidney and liver are functioning well.

Exclusion Criteria

Pregnant or nursing females

You are currently struggling with alcohol or drug addiction.

I need continuous treatment with a strong CYP3A inhibitor or inducer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either zanubrutinib or bendamustine plus rituximab, with specific regimens depending on cohort assignment

Up to 27 cycles (each cycle is 28 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Open-label extension (optional)

Participants may continue receiving zanubrutinib until unacceptable toxicity or disease progression

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Rituximab
• Zanubrutinib

Trial Overview The study tests Zanubrutinib's effectiveness against Bendamustine plus Rituximab in treating CLL/SLL without prior treatments. It measures how long patients stay disease-free as judged by an independent review. Participants are randomly assigned to receive either the new therapy or the existing one.

How Is the Trial Designed?

Group I: Cohort 3: Venetoclax + Zanubrutinib Experimental Treatment 2 Interventions

Approximately 110 participants, 50 without del17p and 60 with del\[17p\] or TP53 mutation will receive zanubrutinib plus venetoclax; Participants will also receive zanubrutinib starting on Cycle 1 Day 1 then daily for a minimum of 27 cycles, or until unacceptable toxicity or disease progression, whichever occurs first. Participants will receive venetoclax starting Cycle 4 Day 1 according to a 5-week dose-up schedule then daily until unacceptable toxicity, disease progression, or for a maximum of 24 cycles. Each cycle is 28 days. (Arm D)

Group II: Cohort 2: Zanubrutinib Experimental Treatment 1 Intervention

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm C)

Group III: Cohort 1a (China only): Zanubrutinib Experimental Treatment 1 Intervention

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A, China only)

Group IV: Cohort 1a (China only): Bendamustine + Rituximab Experimental Treatment 2 Interventions

Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B, China only)

Group V: Cohort 1: Zanubrutinib Experimental Treatment 1 Intervention

Participants will receive zanubrutinib until unacceptable toxicity or disease progression (Arm A)

Group VI: Cohort 1: Bendamustine + Rituximab Experimental Treatment 2 Interventions

Participants will receive bendamustine plus rituximab for up to six 28-day cycles (Arm B)

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

In a study of 100 patients with rituximab-refractory indolent B-cell lymphoma, single-agent bendamustine demonstrated a high overall response rate of 75%, with a median duration of response of 9.2 months.

While bendamustine was effective, it also caused significant side effects, including hematologic toxicities like neutropenia (61%) and non-hematologic issues such as nausea (77%) and infections (69%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Kahl, BS., Bartlett, NL., Leonard, JP., et al.[2021]

Oral rolapitant (180 mg) is effective in preventing delayed chemotherapy-induced nausea and vomiting (CINV) in adults undergoing highly or moderately emetogenic chemotherapy, showing benefits over multiple cycles of treatment.

Rolapitant has a similar tolerability profile to placebo and does not interact with CYP3A4, which means it does not require dose adjustments for dexamethasone, making it a safer option for patients on other medications that are metabolized by this enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rolapitant: A Review in Chemotherapy-Induced Nausea and Vomiting. Heo, YA., Deeks, ED.[2019]

In a study of 61 patients with non-Hodgkin lymphoma undergoing bendamustine-based chemotherapy, both granisetron and palonosetron effectively controlled chemotherapy-induced nausea and vomiting (CINV), with complete control achieved in all patients during the acute phase.

Granisetron monotherapy was found to be as effective and safe as palonosetron combination therapy for preventing delayed CINV, suggesting that granisetron alone could be a cost-effective option for managing CINV in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of antiemetic effects of granisetron and palonosetron in patients receiving bendamustine-based chemotherapy. Uchida, M., Nakamura, T., Makihara, Y., et al.[2019]

Rolapitant (Varubi) is effective in preventing chemotherapy-induced nausea and vomiting, providing a new option for patients undergoing cancer treatment.

The drug works by blocking neurokinin-1 (NK1) receptors, which play a key role in the vomiting reflex, thus improving the quality of life for patients during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rolapitant (Varubi): A Substance P/Neurokinin-1 Receptor Antagonist for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Goldberg, T., Fidler, B., Cardinale, S.[2020]

In a study of 32 classical Hodgkin's lymphoma patients, 47% experienced inadequate control of chemotherapy-induced nausea and vomiting (CINV) with palonosetron and dexamethasone, leading to a switch to netupitant and dexamethasone, which resulted in 53.3% achieving proper CINV control for subsequent cycles.

The switch to NEPA (netupitant/palonosetron) did not increase adverse events compared to the previous treatment, indicating that NEPA is well tolerated and does not interact negatively with standard chemotherapy agents like ABVD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of netupitant/palonosetron and dexamethasone in classical Hodgkin's lymphoma patients with inadequate chemotherapy-induced nausea and vomiting prophylaxis with palonosetron and dexamethasone: a single-center real-life experience. Zilioli, VR., Muzi, C., Minga, P., et al.[2020]

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]

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 study of 34 patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), maintenance therapy with lenalidomide after bendamustine and rituximab (BR) did not significantly improve progression-free survival (PFS), which was 18.3 months compared to 15.2 months without maintenance.

The study highlighted challenges with lenalidomide maintenance due to hematological and infectious toxicities, as only 6 out of 19 patients completed the intended 12 cycles, suggesting that lenalidomide may be more effective in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. Chang, JE., Havighurst, T., Kim, K., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21844497/

Bendamustine combined with rituximab in patients ... The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32969597/

Efficacy of bendamustine and rituximab in unfit patients with ... We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03609593

Study Details | NCT03609593 | Bendamustine/rituximab ... The purpose of this study is to determine the efficacy of bendamustine and rituximab (BR) followed by venetoclax for 12 months. The total time on therapy is ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0037196308001224

Bendamustine in Chronic Lymphocytic Leukemia and ... Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01754870

Phase II Study of Bendamustine and Rituximab Induction ... Bendamustine is a recently FDA-approved agent with significant activity in CLL/SLL, including significant activity in the setting of fludarabine-refractory ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02491398

Efficacy and Safety of Bendamustine Plus Rituximab in ... This study is intended for Chronic Lymphocytic Leukemia patients who have already undergone a first or second treatment with drugs named bendamustine and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01569295

NCT01569295 | Study Evaluating the Efficacy and Safety of ... Idelalisib in Combination with Bendamustine and Rituximab Improves Overall Survival in Patients with Relapsed/Refractory CLL: Interim Results of a Phase 3 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9868021/

Safety and Efficacy of Bendamustine and Rituximab (BR) ... BR is an effective and safe regimen in the first-line treatment of CLL. Unmutated-CLL patients have inferior EFS than mutated-CLL patients.

9. personalizedmedonc.com personalizedmedonc.com/special-issues/faculty-perspectives/march-2013-vol-4-no-2/first-article-efficacy-of-bendamustine-in-chronic-lymphocytic-leukemia-2

Efficacy of Bendamustine in Chronic Lymphocytic Leukemia ... The next article in this series will discuss the safety data in patients with CLL and NHL reported in the registration studies cited in the bendamustine US ...