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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining two drugs, nemtabrutinib and rituximab, to treat mantle cell lymphoma, a cancer affecting white blood cells. Nemtabrutinib (also known as MK-1026 or ARQ 531) is a kinase inhibitor that stops cancer cells from growing, while rituximab helps the immune system target and destroy them. The goal is to determine if using these drugs together can kill more cancer cells than other treatments. The trial seeks participants with mantle cell lymphoma that requires treatment and who have not received prior systemic anticancer therapies. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

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.

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

Research has shown that nemtabrutinib, when combined with rituximab, was generally safe in earlier studies. Most patients tolerated it well, and some experienced tumor reduction. However, nemtabrutinib remains under investigation and is still considered experimental. Rituximab, a well-known drug used to treat certain cancers, has a well-established safety record. The combination of these treatments aims to attack cancer cells more effectively. As with any treatment, side effects may occur, so discussing any concerns with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nemtabrutinib and rituximab for treating mantle cell lymphoma because it offers a unique approach compared to existing therapies. While standard treatments often involve chemotherapy and targeted therapies like BTK inhibitors, nemtabrutinib is a novel BTK inhibitor that could potentially be more effective or have fewer side effects. This combination also employs rituximab, a well-established monoclonal antibody that enhances the immune system's ability to fight cancer. By combining these two treatments, there's hope for a more comprehensive attack on cancer cells, potentially leading to better outcomes for patients.

What evidence suggests that nemtabrutinib and rituximab could be effective for mantle cell lymphoma?

Research has shown that nemtabrutinib has promising effects against tumors, particularly in blood cancers like mantle cell lymphoma. As a kinase inhibitor, it blocks a protein called BTK, which is often found in high amounts in certain cancer cells. Blocking BTK can help stop the cancer from growing and spreading.

Rituximab is a well-known treatment for mantle cell lymphoma. It works by attaching to a specific protein on cancer cells, aiding the immune system in finding and destroying them. Studies indicate that adding rituximab to other treatments can improve survival rates. In this trial, participants will receive a combination of nemtabrutinib and rituximab, which may be more effective in treating mantle cell lymphoma than using each treatment alone. ^{2 3 6 7 8}

Who Is on the Research Team?

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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

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

Platelets ≥ 75,000/mm^3 without bone marrow involvement, platelets ≥ 30,000/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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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 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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03162536

NCT03162536 | A Study of Nemtabrutinib (MK-1026) in ...

Mantle Cell Lymphoma (MCL) participants who have failed at least 2 prior systemic therapies receive up to 65 mg of nemtabrutinib per day orally in each cycle ( ...

2.

aacrjournals.org

aacrjournals.org/mct/article/22/12_Supplement/B170/730349/Abstract-B170-The-in-vitro-anti-tumor-activity-of

Abstract B170: The in vitro anti-tumor activity of the multi ...

Results. The median IC50 for nemtabrutinib was 1.4 µM (95%CI, 0.8-2.3 µM) across all 54 lymphoma cell lines tested. Higher activity was found ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8954159/

Relapsed/Refractory Mantle Cell Lymphoma: Beyond BTK ...

Outcomes after progression on BTKi are extremely poor, with a median overall survival (OS) of 6 to 10 months. Certain therapies, such as chimeric antigen ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S0006497121023867

Preliminary Efficacy and Safety of MK-1026, a Non- ...

MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy.

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mayo.edu

mayo.edu/research/clinical-trials/cls-20529145

Efficacy and Safety of Nemtabrutinib (MK-1026) in ...

The purpose of this study is to evaluate the safety and effectiveness of MK-1026 (formerly ARQ 531) in participants with hematologic malignancies.

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clinicaltrials.gov

clinicaltrials.gov/study/NCT06572618

Nemtabrutinib With Rituximab for the Treatment of Patients ...

This may help the immune system kill cancer cells. Giving nemtabrutinib with rituximab may kill more cancer cells in patients with mantle cell lymphoma.

7.

clinical-lymphoma-myeloma-leukemia.com

clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)00237-3/fulltext

Treatment Landscape of Relapsed/Refractory Mantle Cell ...

In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of ...

8.

jhoonline.biomedcentral.com

jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00914-1

Emerging therapies in mantle cell lymphoma

We provide a comprehensive review of past and ongoing studies that will likely significantly impact our approach to MCL treatment.