Zanubrutinib + Bendamustine + Rituximab for Waldenstrom Macroglobulinemia

(ZEBRA Trial)

Recruiting at 2 trial locations

Overseen By Andrew Branagan, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Warfarin, Strong CYP3A inducers

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 15 cycles

55 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 certain treatments like systemic immunosuppressants, warfarin, or strong CYP3A inducers. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Zanubrutinib, Bendamustine, and Rituximab for treating Waldenstrom Macroglobulinemia?

Research shows that the combination of Bendamustine and Rituximab is effective for treating Waldenstrom Macroglobulinemia, with high response rates and longer progression-free survival compared to other treatments. This suggests that adding Zanubrutinib, which is effective in similar conditions, could enhance the treatment's effectiveness. ^{1 2 3 4 5}

Is the combination of Zanubrutinib, Bendamustine, and Rituximab safe for treating Waldenstrom Macroglobulinemia?

The combination of Bendamustine and Rituximab has been found to be generally safe for treating Waldenstrom Macroglobulinemia, with common side effects including neutropenia (low white blood cell count) in some patients. No significant safety concerns were noted, and the treatment was well-tolerated, leading to effective disease control. ^{1 2 3 4 5}

What makes the drug combination of Zanubrutinib, Bendamustine, and Rituximab unique for treating Waldenstrom Macroglobulinemia?

This drug combination is unique because it includes Zanubrutinib, a second-generation BTK inhibitor, which is generally well-tolerated and induces deeper remissions compared to other treatments like ibrutinib. Additionally, combining it with Bendamustine and Rituximab, which are effective in fixed-duration regimens, may offer a novel approach to achieving rapid and deep responses in patients with Waldenstrom Macroglobulinemia. ^{1 2 3 4 6}

What is the purpose of this trial?

The purpose of this study is to determine the very good partial response (VGPR) or better rate in participants with Waldenström macroglobulinemia (WM). The names of the study drugs involved in this study are as follows: zanubrutinib, bendamustine, and rituximab.

Research Team

Andrew Branagan, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for individuals with Waldenstrom Macroglobulinemia, a type of cancer that affects white blood cells and can cause anemia, thickened blood, and other issues. The study is seeking participants who have not been treated before.

Inclusion Criteria

Ability to understand and sign a written informed consent document

My cancer has a specific genetic mutation (MYD88 or CXCR4).

My organ and bone marrow functions are within required levels.

Exclusion Criteria

I am not on any immune-suppressing drugs, except for low-dose steroids.

Pregnant, breastfeeding, planning pregnancy, or breastfeeding during the study

History of non-compliance to medical regimens

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib orally daily, bendamustine intravenously on days 1 and 2, and rituximab intravenously on day 1 of cycles 1-4, for up to 15 cycles

15 cycles

Multiple visits per cycle for drug administration

Follow-up

Participants are monitored for safety, tolerability, and response to treatment

5 years

Treatment Details

Interventions

• Bendamustine
• Rituximab
• Zanubrutinib

Trial Overview The study aims to evaluate the effectiveness of a combination treatment using zanubrutinib, bendamustine, and rituximab in achieving a very good partial response or better in patients with WM.

Participant Groups

Group I: Zanubrutinib + Bendamustine + Rituximab Experimental Treatment 3 Interventions

Zanubrutinib will be taken orally once daily on days 1-28 of cycles 1-15. Bendamustine will be given by intravenous infusion over about 10 to 60 minutes on days 1 and 2 of cycles 1 to 4. Rituximab will be given by intravenous infusion over about 30 minutes on day 1 of cycles 1 to 4. Drug diaries will be provided to participants to document information about the study treatment being taken.

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Findings from Research

In a study of 160 patients with Waldenstrom macroglobulinemia, the bendamustine-rituximab (BR) regimen showed a trend towards longer progression-free survival (PFS) compared to dexamethasone, rituximab plus cyclophosphamide (DRC), with 2-year PFS rates of 88% for BR versus 61% for DRC, although the difference was not statistically significant (p=0.07).

Both treatment regimens had comparable overall response rates and grade ≥3 adverse events, indicating similar safety profiles, and the effectiveness of both regimens was not influenced by the presence of the MYD88L265P mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Paludo, J., Abeykoon, JP., Shreders, A., et al.[2018]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. [2018]

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

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia: Patient outcomes and impact of bendamustine dosing. [2023]

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

Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia. [2022]

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

Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. [2022]

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

Assessment of fixed-duration therapies for treatment-naïve Waldenström macroglobulinemia. [2023]

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

Report of consensus panel 1 from the 11th International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients. [2023]