Zanubrutinib vs Bendamustine + Rituximab for Chronic Lymphocytic Leukemia

(SEQUOIA Trial)

Recruiting at 285 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)

590 Participants Needed

Trial Summary

What is the purpose of this trial?

To compare efficacy between zanubrutinib versus bendamustine and rituximab in patients with previously untreated CLL/SLL, as measured by progression free survival assess by Independent Central Review.

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.

What data supports the effectiveness of the drug combination of bendamustine and rituximab for chronic lymphocytic leukemia?

Research shows that the combination of bendamustine and rituximab is effective in treating chronic lymphocytic leukemia, especially in patients who have relapsed or are resistant to other treatments. This combination has demonstrated high response rates and is considered a standard care option for managing this condition. ^{1 2 3 4 5}

Is the combination of Bendamustine and Rituximab safe for humans?

Bendamustine, used in combination with Rituximab, has been studied for safety in patients with non-Hodgkin lymphoma, showing that it can be safely administered with anti-nausea medications like granisetron and palonosetron, which help manage chemotherapy-induced nausea and vomiting. ^{6 7 8 9 10}

How does the drug zanubrutinib differ from bendamustine plus rituximab for chronic lymphocytic leukemia?

Zanubrutinib is a next-generation drug that specifically targets a protein called Bruton's tyrosine kinase, which is involved in the growth of cancer cells. It has shown better progression-free survival compared to the combination of bendamustine and rituximab, which is a more traditional chemotherapy and antibody treatment. ^{2 4 11 12 13}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

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

Measurable disease by imaging

My bone marrow is working well.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

References

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

Is bendamustine an ideal partner for rituximab in the management of relapsed chronic lymphocytic leukemia? Results of a multicenter Phase II trial. [2012]

2. England 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. [2018]

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

Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. [2022]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia accompanied by renal failure]. [2019]

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

Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. [2022]

6. United States 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. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Comparison of antiemetic effects of granisetron and palonosetron in patients receiving bendamustine-based chemotherapy. [2019]

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

Rolapitant (Varubi): A Substance P/Neurokinin-1 Receptor Antagonist for the Prevention of Chemotherapy-Induced Nausea and Vomiting. [2020]

9. England 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. [2020]

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

Rolapitant: A Review in Chemotherapy-Induced Nausea and Vomiting. [2019]

11. 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]

12. Italy pubmed.ncbi.nlm.nih.gov

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. [2019]

13. 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]