Nemtabrutinib + Rituximab for Mantle Cell Lymphoma

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A4 inducers, Corticosteroids

Disqualifiers: Unstable cardiac disease, Active infection, 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: 6

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests how well nemtabrutinib works with rituximab for the treatment of patients with mantle cell lymphoma. Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cell (a type of white blood cells) cancers such as mantel cell lymphoma at abnormal levels. This may help keep cancer cells from growing and spreading. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nemtabrutinib with rituximab may kill more cancer cells in patients with mantle cell lymphoma.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on anticoagulants, your PT and aPTT must be within the therapeutic range. Also, if you are on antiretroviral therapy for HIV, it should not include strong CYP3A4 inducers.

What data supports the effectiveness of the drug combination Nemtabrutinib and Rituximab for treating Mantle Cell Lymphoma?

Rituximab, when combined with other drugs like bendamustine or ibrutinib, has shown effectiveness in treating mantle cell lymphoma, improving progression-free survival (the time during which the disease does not get worse). Additionally, Bruton tyrosine kinase inhibitors, a class of drugs to which Nemtabrutinib belongs, are considered an effective treatment strategy for mantle cell lymphoma. ^{1 2 3 4 5}

What safety data exists for Nemtabrutinib + Rituximab in humans?

Bruton's tyrosine kinase inhibitors, like Nemtabrutinib, have shown a well-tolerated safety profile in treating B-cell malignancies, including mantle cell lymphoma. Rituximab, used in combination with other drugs, has been associated with common side effects like neutropenia (low white blood cell count), anemia (low red blood cell count), high blood pressure, and infections. ^{1 3 6 7 8}

What makes the drug combination of Nemtabrutinib and Rituximab unique for treating mantle cell lymphoma?

Nemtabrutinib is a novel Bruton tyrosine kinase inhibitor, which may offer a new approach for patients with mantle cell lymphoma, especially those who have not responded well to other treatments. This combination with Rituximab could provide a more targeted therapy option compared to traditional chemotherapy regimens. ^{1 2 3 9 10}

Research Team

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with mantle cell lymphoma. Participants should have this type of cancer to be eligible. Specific inclusion and exclusion criteria are not listed, but typically these would cover health status, prior treatments, and other medical conditions.

Inclusion Criteria

Platelets ≥ 75,000/mm^3 without bone marrow involvement, platelets ≥ 30,000/mm^3 with bone marrow involvement

ANC ≥ 1,000/mm^3 without bone marrow involvement, ANC ≥ 500/mm^3 with bone marrow involvement

Aspartate aminotransferase (AST) ≤ 2.5 x ULN

Exclusion Criteria

I take more than 20 mg/day of prednisone or its equivalent.

Any other condition that would contraindicate the patient's participation in the clinical study

I have a history of severe bleeding problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Patients receive nemtabrutinib orally once per day and rituximab intravenously on specified days. Cycles repeat every 28 days for up to 6 cycles.

24 weeks

4 visits (in-person) per cycle

Maintenance

Patients continue to receive nemtabrutinib orally once per day and rituximab intravenously on event numbered cycles. Cycles repeat every 28 days for up to 24 cycles.

96 weeks

1 visit (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days, then every 3 months for the first 2 years, and every 6 months for the third year.

3 years

Periodic visits (in-person)

Treatment Details

Interventions

• Nemtabrutinib
• Rituximab

Trial Overview The trial is testing the effectiveness of combining nemtabrutinib, a kinase inhibitor that blocks proteins linked to B-cell cancers, with rituximab, an antibody that helps the immune system target cancer cells. It's a phase II study which means it's checking how well these drugs work together.

Participant Groups

Group I: Treatment (nemtabrutinib and rituximab) Experimental Treatment 5 Interventions

INDUCTION: Patients receive nemtabrutinib PO QD on days 1-28 of each cycle and rituximab IV on days 1, 8, 15 and 22 of cycle 1 and on day 1 of subsequent cycles. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive nemtabrutinib PO QD on days 1-28 of each cycle and rituximab IV on day 1 of event numbered cycles. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue to receive nemtabrutinib PO QD in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy during screening and may undergo throughout the trial and PET-CT scan and blood sample collection throughout the study.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The combination of bendamustine and rituximab (BR) showed a high overall response rate of 90% in 63 patients with mantle cell or low-grade lymphomas, with a complete remission rate of 60%.

The median progression-free survival was 24 months, indicating that BR is an effective treatment option for patients in their first to third relapse or refractory to previous treatments, although myelosuppression was noted as a significant side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. Rummel, MJ., Al-Batran, SE., Kim, SZ., et al.[2022]

In a phase 2 study involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib and rituximab resulted in an impressive 88% objective response rate, with 44% of patients achieving a complete response.

The treatment was generally well tolerated, with the most common serious side effect being atrial fibrillation in 12% of patients, indicating that while effective, monitoring for cardiac issues is important during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Wang, ML., Lee, H., Chuang, H., et al.[2021]

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 study of 57 patients with untreated mantle-cell lymphoma, a treatment regimen of four cycles of R-CHOP followed by yttrium-90 (90Y)-ibritumomab tiuxetan resulted in an overall response rate of 82%, indicating strong efficacy.

The median time to treatment failure was 34.2 months, and the estimated 5-year overall survival rate was 73%, demonstrating that this combination therapy is well-tolerated and offers promising outcomes compared to historical data with six cycles of R-CHOP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. Smith, MR., Li, H., Gordon, L., et al.[2021]

In a network meta-analysis of three randomized controlled trials involving 1459 patients with newly diagnosed mantle-cell lymphoma (MCL) ineligible for intensive therapy, the combination of ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) compared to other regimens like VR-CAP and R-CHOP.

Ibru + BR had a 94.9% probability of being the best treatment option for prolonging PFS, with no significant differences in adverse events compared to the other treatment regimens, indicating its efficacy and safety for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. Sheng, Z., Wang, L.[2023]

In a study of 1390 patients with mantle cell lymphoma (MCL) treated between 2013-2015, the most common first-line treatment was chemoimmunotherapy with bendamustine/rituximab (BR), which showed a 24-month overall survival (OS) rate of 73%.

The study found that patients experiencing three or more adverse events (AEs) had nearly four times higher monthly treatment costs compared to those with fewer AEs, highlighting the significant economic burden associated with increased AEs in MCL treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence on survival, adverse events, and health care burden in Medicare patients with mantle cell lymphoma. Goyal, RK., Jain, P., Nagar, SP., et al.[2021]

Acalabrutinib (Calquence®) has received accelerated approval from the US FDA for treating mantle cell lymphoma, based on promising results from a phase II study.

Phase III trials are currently ongoing for acalabrutinib in mantle cell lymphoma and chronic lymphocytic leukaemia, indicating its potential for broader application in treating hematological cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: First Global Approval. Markham, A., Dhillon, S.[2018]

Bruton's tyrosine kinase inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are effective and well-tolerated treatment options for patients with mantle cell lymphoma who have already undergone one line of therapy.

These inhibitors offer a promising alternative for patients who experience relapse or drug resistance after initial chemo-immunotherapy, highlighting the need for novel treatment strategies in this aggressive lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. Hanna, KS., Campbell, M., Husak, A., et al.[2021]

In a phase II study involving 50 previously untreated patients with indolent mantle cell lymphoma (MCL), the combination of ibrutinib and rituximab resulted in an impressive 80% complete response rate after 12 treatment cycles.

The treatment also led to undetectable minimal residual disease (MRD) in 87% of patients, allowing 69% of evaluable patients to safely discontinue ibrutinib after 2 years, although caution is advised for those with TP53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial. Giné, E., de la Cruz, F., Jiménez Ubieto, A., et al.[2022]

The Mantle Cell Lymphoma International Prognostic Index-Combined, which includes the Ki67 index and clinical factors, is crucial for risk stratification at diagnosis, helping to predict patient outcomes more accurately.

New targeted therapies, such as Bruton tyrosine kinase inhibitors and CAR T-cell therapies, show promising efficacy in treating mantle cell lymphoma, especially in high-risk patients, and may lead to improved survival rates after traditional treatments fail.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Directions for Mantle Cell Lymphoma in 2022. Kumar, A., Eyre, TA., Lewis, KL., et al.[2022]

References

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

Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. [2021]

3. 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]

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

Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. [2021]

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

Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis. [2023]

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

Real-world evidence on survival, adverse events, and health care burden in Medicare patients with mantle cell lymphoma. [2021]

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

Acalabrutinib: First Global Approval. [2018]

8. England pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. [2021]

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

Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial. [2022]

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

New Directions for Mantle Cell Lymphoma in 2022. [2022]