Zanubrutinib + Bendamustine + Rituximab for Waldenstrom Macroglobulinemia

(ZEBRA Trial)

Recruiting at 3 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of three drugs—zanubrutinib, bendamustine, and rituximab—in treating Waldenström macroglobulinemia (WM), a rare blood cancer. Researchers are particularly interested in the number of participants who experience significant improvement. Individuals diagnosed with WM who have symptoms such as fatigue, weight loss, or night sweats, but have not yet started treatment, might be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research shows that the combination of zanubrutinib, bendamustine, and rituximab is generally well-tolerated by patients with Waldenström macroglobulinemia. Previous studies found that this combination can lead to significant improvement in patients. Adverse events, or unwanted side effects, are manageable. While some side effects might occur, they are usually not severe and can be controlled with standard medical care.

Studies on bendamustine and rituximab together have found them to be safe and effective as a treatment plan. This suggests a similar level of safety can be expected from this combination. Overall, the available evidence indicates that the treatment is reasonably safe, with generally manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of zanubrutinib, bendamustine, and rituximab for treating Waldenstrom Macroglobulinemia because it offers a fresh approach compared to existing treatments. Zanubrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor, which targets a specific protein essential for the growth of cancer cells, potentially offering more targeted and effective treatment. Unlike standard therapies, which often rely on chemotherapy alone, this combination leverages the strengths of both targeted therapy and immunotherapy, aiming for a more comprehensive attack on the cancer cells. This strategy may improve outcomes and reduce some of the side effects typically associated with traditional chemotherapy.

What evidence suggests that this trial's treatments could be effective for Waldenstrom Macroglobulinemia?

In this trial, participants will receive a combination of zanubrutinib, bendamustine, and rituximab to treat Waldenström macroglobulinemia (WM). Research has shown that this combination is promising, leading to significant deep remission rates, with many patients experiencing a strong reduction in disease symptoms. Zanubrutinib has proven particularly effective compared to other treatments like ibrutinib for WM. Rituximab, included in this combination, is already a standard treatment for WM and has demonstrated effectiveness. Overall, this treatment combination offers a hopeful option for better managing WM. ^{1 3 5 6 7}

Who Is on the Research Team?

Andrew Branagan, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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

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

History of non-compliance to medical regimens

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/6324/528257/Phase-II-Clinical-Study-of-Zanubrutinib-Combined

Phase II Clinical Study of Zanubrutinib Combined with ... The ZBR regimen reached significant deep remission rates in newly diagnosed symptomatic WM patients with manageable adverse events.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06561347

NCT06561347 | Zanubrutinib, Bendamustine, Rituximab ... The purpose of this study is to determine the very good partial response (VGPR) or better rate in participants with Waldenström macroglobulinemia (WM).

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124091511

Phase II Clinical Study of Zanubrutinib Combined with ... The ZBR regimen reached significant deep remission rates in newly diagnosed symptomatic WM patients with manageable adverse events.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10485051/

Efficacy and safety of front-line treatment regimens for ... Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.7559

Efficacy and safety of zanubrutinib versus rituximab-based ... ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM).

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05979948?cond=%22Macroglobulinemia%22&intr=%22bendamustine%20hydrochloride%22&viewType=Table&rank=6

A Phase 2 Clinical Trial to Evaluate Zanubrutinib ... A phase of research to describe clinical trials that gather more information about a drug's safety and effectiveness by studying different populations and ...

7. beonemedinfo.com beonemedinfo.com/CongressDocuments/Castillo_BGB-3111_WM_Ind_Comp_EHA_Poster_2021.pdf

efficacy and safety of zanubrutinib versus rituximab-based ... Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenstrom macroglobulinemia. Leuk Lymphoma. 2015;56(9):2637-2642. 2 ...