Nemtabrutinib for Chronic Lymphocytic Leukemia

Not currently recruiting at 141 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme LLC

Disqualifiers: Hepatitis B/C, Malignancy, Bleeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 49 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), both types of blood cancer. The researchers aim to determine if nemtabrutinib, an experimental drug, can help patients live longer without their cancer progressing or returning. Participants will receive either nemtabrutinib or a combination of standard treatments like bendamustine and rituximab. Those diagnosed with CLL or SLL who have not yet received treatment might be suitable for this trial. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to potentially groundbreaking treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that nemtabrutinib, a treatment for certain blood cancers, has a promising safety record from earlier studies. In trials with patients who have very relapsed or difficult-to-treat conditions like chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), nemtabrutinib was generally well-tolerated. Most patients experienced mild to moderate side effects that were manageable.

Other treatments in this trial, such as fludarabine, cyclophosphamide, and rituximab, have long been used in cancer treatments. They have established safety records but can also cause side effects like nausea or low blood cell counts. It is important to consult a healthcare provider to determine if joining a trial is appropriate. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for leukemia?

Researchers are excited about nemtabrutinib for chronic lymphocytic leukemia because it offers a new way to approach the condition. Unlike the standard treatments, which often include combinations like fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR), nemtabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor. This means it specifically targets and blocks BTK, a protein essential for the survival and growth of leukemia cells. Additionally, nemtabrutinib is conveniently administered as a daily oral tablet, potentially offering a more manageable option for patients compared to traditional intravenous therapies. This unique mechanism and delivery method could lead to more effective and easier-to-manage treatment options for patients.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research shows that nemtabrutinib, a treatment under study in this trial, holds promise for treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Studies indicate it can be effective even for patients whose cancer has returned after treatment. This treatment targets specific proteins in cancer cells, helping to stop the cancer from growing. Early findings suggest that nemtabrutinib is generally well-tolerated by patients, with manageable side effects. These results are encouraging for those considering joining a clinical trial for this treatment. ^{1 2 3 4 6}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with untreated CLL/SLL who don't have TP53 mutations. They must need treatment, be able to take pills, and not have had major surgery recently or active hepatitis. People with other progressing cancers or severe bleeding disorders can't join.

Inclusion Criteria

I have been diagnosed with CLL/SLL and need treatment.

I can swallow and keep down pills.

I have CLL/SLL without TP53 mutations, and my 11q and IGHV status are known.

Exclusion Criteria

I have no progressing cancer or treated cancer in the last 3 years, except for certain skin cancers or localized cancers that were treated.

I am still recovering from major surgery or have ongoing complications.

I have a history of severe bleeding disorders.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Nemtabrutinib or standard chemoimmunotherapy (FCR or BR) for CLL/SLL

Up to approximately 49 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 94 months

What Are the Treatments Tested in This Trial?

Interventions

• Bendamustine
• Cyclophosphamide
• Fludarabine
• Nemtabrutinib
• Riabni
• Rituximab
• Rituximab biosimilar
• Ruxience
• Truxima

Trial Overview The study compares Nemtabrutinib's effectiveness and safety against standard chemoimmunotherapy (FCR/BR) in extending the time patients live without disease progression. Participants will either receive Nemtabrutinib or a combination of chemotherapy drugs plus Rituximab.

How Is the Trial Designed?

Group I: Nemtabrutinib Experimental Treatment 1 Intervention

Administered daily via oral tablet.

Group II: FCR or BR Active Control 7 Interventions

Investigator's choice of fludarabine plus cyclophosphamide plus rituximab (FCR) OR bendamustine plus rituximab (BR). Participants will receive either rituximab or specified approved rituximab biosimilar.

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?

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a study of 34 patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), maintenance therapy with lenalidomide after bendamustine and rituximab (BR) did not significantly improve progression-free survival (PFS), which was 18.3 months compared to 15.2 months without maintenance.

The study highlighted challenges with lenalidomide maintenance due to hematological and infectious toxicities, as only 6 out of 19 patients completed the intended 12 cycles, suggesting that lenalidomide may be more effective in earlier treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: A Wisconsin Oncology Network Study. Chang, JE., Havighurst, T., Kim, K., et al.[2018]

In a phase II study of 10 patients with relapsed chronic lymphocytic leukemia (CLL), the combination of ofatumumab and bendamustine resulted in an overall response rate of 40% and a complete response rate of 20%.

The study was halted early due to unexpected adverse events, including infusion-related reactions, infections, and neurotoxicity, highlighting safety concerns with this treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. Ujjani, C., Ramzi, P., Gehan, E., et al.[2019]

Chronic lymphocytic leukemia (CLL) treatment varies based on patient age and fitness, with younger patients typically receiving the FCR regimen and older, fit patients being treated with BR or bendamustine plus ofatumumab.

New oral medications like idelalisib and ibrutinib have shown impressive efficacy and tolerability in patients with high-risk genetic factors or relapsed CLL, indicating a shift in treatment strategies towards these novel agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. Tausch, E., Stilgenbauer, S.[2018]

In a phase 3 study involving 447 treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma, bendamustine plus rituximab (BR) was found to be noninferior to standard rituximab-chemotherapy regimens (R-CHOP/R-CVP) in achieving complete response rates (31% vs 25%).

While BR showed a higher overall response rate (97% vs 91%), it also had a higher incidence of vomiting and drug-hypersensitivity reactions compared to standard therapies, indicating a need to consider safety profiles when choosing treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Flinn, IW., van der Jagt, R., Kahl, BS., et al.[2022]

In a study of 145 patients with chronic lymphoid leukemia (CLL) and indolent non-Hodgkin lymphoma treated with bendamustine and rituximab, 25% experienced late onset neutropenia (LON), indicating a significant risk associated with this treatment.

The incidence of LON was particularly high in patients with follicular lymphoma, leading to treatment discontinuation in many cases, highlighting the need for close monitoring and prophylactic measures during and after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Description of late onset neutropenia in indolent lymphoma patients treated with bendamustine plus rituximab. Verriere, B., Gastaud, L., Chamorey, E., et al.[2018]

In a study involving 561 patients with chronic lymphocytic leukaemia, the standard treatment of fludarabine, cyclophosphamide, and rituximab showed a longer median progression-free survival of 55.2 months compared to 41.7 months for the bendamustine and rituximab combination, indicating that the standard therapy is more effective.

However, the bendamustine and rituximab combination was associated with significantly fewer severe side effects, such as neutropenia and infections, making it a potentially safer alternative for patients, especially those over 65 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Eichhorst, B., Fink, AM., Bahlo, J., et al.[2022]

Chronic lymphocytic leukemia (CLL) is a complex B-cell cancer that often relapses after traditional treatments, highlighting the need for new therapeutic options.

Recent advancements in CLL treatment include a variety of novel drugs such as ibrutinib and idelalisib, which are showing promise in improving patient outcomes compared to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for chronic lymphocytic leukemia. Wu, M., Akinleye, A., Zhu, X.[2021]

Bendamustine is a unique cancer treatment that combines alkylating and antimetabolite properties, making it effective against certain blood cancers like chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

It has been approved by the US FDA for patients whose cancer has not responded to or has progressed after rituximab treatment, and it can be used alone or in combination with other therapies, showing promising efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Ujjani, C., Cheson, BD.[2015]

Bendamustine shows high efficacy in treating Hodgkin's disease and non-Hodgkin's lymphoma, with objective response rates ranging from 61% to 97%, and it also demonstrates improved complete response rates in multiple myeloma compared to melphalan.

The drug has a favorable safety profile, with common side effects being hematological events and gastrointestinal disturbances, but it has a low likelihood of causing hair loss, making it a potentially more tolerable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine. Balfour, JA., Goa, KL.[2018]

In pivotal study GO29365 involving patients with relapsed/refractory diffuse large B-cell lymphoma, polatuzumab vedotin (1.8 mg/kg) combined with bendamustine-rituximab showed a favorable risk/benefit profile, supporting its use for six cycles.

Supportive studies indicated that higher exposure to polatuzumab vedotin increased response rates but also raised the risk of side effects like peripheral neuropathy and anemia, suggesting that dosing should not fall below 1.8 mg/kg to maintain efficacy while managing safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma. Lu, T., Gibiansky, L., Li, X., et al.[2021]

In the MURANO study, patients with relapsed/refractory chronic lymphocytic leukemia who received fixed-duration venetoclax-rituximab showed significantly better progression-free survival (PFS) and overall survival compared to those treated with bendamustine-rituximab, with a median follow-up of 36 months.

The treatment with venetoclax-rituximab resulted in a higher rate of undetectable minimal residual disease (uMRD) at the end of therapy (62% vs. 13%), which was associated with longer PFS, indicating that achieving uMRD is a strong predictor of treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. Kater, AP., Seymour, JF., Hillmen, P., et al.[2019]

In the HELIOS trial involving 578 subjects, the combination of bendamustine/rituximab and ibrutinib (BR-I) resulted in significantly higher systemic exposure to rituximab compared to bendamustine/rituximab with placebo (BR), particularly in the initial treatment cycles.

The study found no significant safety differences between the BR-I and BR groups, suggesting that the enhanced efficacy of BR-I may be achieved without compromising patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. Lavezzi, SM., de Jong, J., Neyens, M., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03162536

NCT03162536 | A Study of Nemtabrutinib (MK-1026) in ... This study aims to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic (PK) of nemtabrutinib (formerly ARQ 531) tablets in selected ...

2. 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.

3. cllsociety.org cllsociety.org/2023/04/ash-2022-efficacy-and-safety-of-nemtabrutinib/

ASH 2022: Efficacy and Safety of Nemtabrutinib, a Wild ... Nemtabrutinib shows promising antitumor activity and a manageable safety profile in highly relapsed/refractory patients with CLL / SLL.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04728893

NCT04728893 | Efficacy and Safety of Nemtabrutinib (MK- ... The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies.

5. 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 ... Nemtabrutinib has shown preclinical and clinical activity in chronic lymphocytic leukemia (CLL), also against tumors bearing mutations ...

6. merckclinicaltrials.com merckclinicaltrials.com/trial/nct04728893/

Efficacy and Safety of Nemtabrutinib in Participants With ... The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies.