Zanubrutinib for Mantle Cell Lymphoma

Recruiting at 225 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: Strong CYP3A4 inhibitors, inducers

Disqualifiers: Cardiovascular disease, Hepatitis, Stroke, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a complete remission (CR) with rituximab works in older adult patients with mantle cell lymphoma (MCL) who have not received treatment in the past (previously untreated). Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to continue administering the drug indefinitely until disease progression. This continuous treatment comes with clinical as well as financial toxicity, which could be especially detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus rituximab therapy, it may be safe and equally effective to stop treatment and restart zanubrutinib upon disease progression rather than continuing indefinitely in previously untreated older adult patients with MCL.

Will I have to stop taking my current medications?

The trial requires that you stop taking any strong CYP3A4 inhibitors or inducers 14 days before starting the study. If you are on these medications, you will need to discontinue them before participating.

Is zanubrutinib safe for humans?

Zanubrutinib is generally well tolerated, but some patients have experienced side effects like diarrhea, infections, and anemia. Severe liver injury has been reported in one case, and some patients discontinued treatment due to adverse effects. Overall, it has shown fewer off-target effects compared to similar drugs. ^{1 2 3 4 5}

How is the drug zanubrutinib unique in treating mantle cell lymphoma?

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that offers higher selectivity and fewer off-target effects compared to first-generation BTK inhibitors, potentially leading to better tolerance and effectiveness in treating mantle cell lymphoma, especially for patients who cannot undergo standard treatments. ^{1 4 5 6 7}

Eligibility Criteria

This trial is for older adults with untreated Mantle Cell Lymphoma (MCL). Eligible participants are those aged 70+ or 60-69 with certain health issues, have measurable disease, and haven't had prior MCL treatments like stem cell transplants, radiation for stage I MCL, systemic treatments, BTK inhibitors or anti-CD20 monoclonal antibodies.

Inclusion Criteria

I have never been treated with BTK inhibitors or anti-CD20 drugs.

I am taking steroids for my lymphoma, but not more than 100mg/day of prednisone or its equivalent, and for no longer than 7 days.

My lymphoma is confirmed to be mantle cell type with specific genetic markers.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive zanubrutinib orally and rituximab intravenously. They undergo bone marrow biopsy and imaging studies.

12 weeks

Multiple visits for drug administration and assessments

Maintenance Therapy

Patients achieving a complete remission are randomized to continuous or intermittent zanubrutinib treatment.

Until disease progression

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

10 years

Every 6 months

Treatment Details

Interventions

• Zanubrutinib (Bruton's Tyrosine Kinase (BTK) Inhibitor)

Trial Overview The study tests continuous versus intermittent Zanubrutinib treatment after complete remission using Rituximab in older patients with MCL. It aims to determine if stopping Zanubrutinib after remission and restarting upon progression is as effective as continuous treatment.

Participant Groups

Group I: Induction therapy (Zanubrutinib, rituximab) Experimental Treatment 12 Interventions

Patients receive zanubrutinib PO and rituximab IV on study. Patients undergo bone marrow biopsy and FDG PET/CT or CT throughout the trial. Patients may also undergo EDG and/or colonoscopy on study as clinically indicated. Patients may optionally undergo blood sample collection throughout the trial.

Group II: Arm A (Zanubrutinib) Experimental Treatment 11 Interventions

Patients receive zanubrutinib PO until first disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial.

Group III: ARM B (Observation) Active Control 11 Interventions

Patients undergo observation until first disease progression and then receive zanubrutinib PO until second disease progression on study. Patients undergo CT or MRI or FDG PET/CT throughout the trial. Patients may optionally undergo blood sample collection throughout the trial.

Zanubrutinib is already approved in China for the following indications:

Approved in China as Brukinsa for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Zanubrutinib, a next-generation Bruton tyrosine kinase inhibitor, shows promise as a targeted therapy for mantle cell lymphoma, particularly for patients who are elderly or have comorbidities and cannot undergo standard treatments.

An ongoing Phase III study is evaluating the safety and efficacy of zanubrutinib combined with rituximab compared to bendamustine with rituximab in patients with untreated mantle cell lymphoma who are not eligible for stem cell transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. Dreyling, M., Tam, CS., Wang, M., et al.[2021]

In a phase 1/2 study involving 32 patients with relapsed/refractory mantle cell lymphoma, zanubrutinib showed a high overall response rate of 84%, with 25% of patients achieving a complete response and a median duration of response of 18.5 months.

Zanubrutinib was generally well tolerated, with the most common adverse events being diarrhea (43.8%) and infections (18.8% experiencing grade ≥3 infections), indicating that while there are side effects, the treatment is effective for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Tam, CS., Opat, S., Simpson, D., et al.[2021]

This case report presents the first documented instance of severe liver injury associated with zanubrutinib, a Bruton's tyrosine kinase inhibitor used in treating B cell malignancies, after 30 months of treatment.

The patient's liver function improved significantly after discontinuing zanubrutinib, highlighting the need for clinical vigilance regarding potential liver toxicity and the importance of stopping the drug if liver injury occurs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib-induced liver injury: a case report and literature review. Atallah, E., Wijayasiri, P., Cianci, N., et al.[2021]

Zanubrutinib, a second-generation BTK inhibitor, has shown an impressive overall response rate of 84% in treating relapsed/refractory mantle cell lymphoma (MCL) based on data from 118 patients in two clinical trials, with a duration of response lasting 14-18 months.

Despite 57% of patients experiencing significant side effects, only 8% discontinued treatment, indicating that zanubrutinib is generally well tolerated and may offer advantages over first-generation BTK inhibitors like ibrutinib due to its higher selectivity and potential for combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanubrutinib: a new BTK inhibitor for treatment of relapsed/refractory mantle cell lymphoma. Weaver, AN., Jimeno, A.[2020]

In a phase II study involving 86 patients with relapsed mantle-cell lymphoma, zanubrutinib demonstrated a high overall response rate of 84%, with 68.6% achieving a complete response after a median follow-up of 18.4 months.

Zanubrutinib was generally well tolerated, with most adverse events being manageable; serious side effects like major bleeding were rare, indicating a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Patients with Relapsed or Refractory Mantle-Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase. Song, Y., Zhou, K., Zou, D., et al.[2021]

A 75-year-old patient developed a severe disseminated cryptococcal infection, leading to pneumonia and meningitis, four months after starting zanubrutinib for Waldenström's macroglobulinemia, highlighting a potential risk of serious infections associated with BTK inhibitors.

Despite initial treatment, the patient's condition worsened, resulting in septic shock and multiorgan failure, suggesting that while zanubrutinib can be effective for certain cancers, it may also compromise immune function, increasing vulnerability to invasive fungal infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia. Patel, D., Sidana, M., Mdluli, X., et al.[2022]

References

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

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma. [2021]

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

Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Zanubrutinib-induced liver injury: a case report and literature review. [2021]

4. Spain pubmed.ncbi.nlm.nih.gov

Zanubrutinib: a new BTK inhibitor for treatment of relapsed/refractory mantle cell lymphoma. [2020]

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

Zanubrutinib: First Approval. [2020]

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

Treatment of Patients with Relapsed or Refractory Mantle-Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase. [2021]

7. England pubmed.ncbi.nlm.nih.gov

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia. [2022]