Nemtabrutinib for Chronic Lymphocytic Leukemia

Recruiting at 109 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

300 Participants Needed

Trial Summary

What is the purpose of this trial?

Researchers are looking for new ways to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). CLL and SLL are types of blood cancer. Researchers want to know if people who take nemtabrutinib compared to those who take the standard treatments in this study will live longer without their cancer growing, spreading or returning (progression free survival).

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.

What data supports the idea that Nemtabrutinib for Chronic Lymphocytic Leukemia is an effective drug?

The available research does not provide specific data on Nemtabrutinib for Chronic Lymphocytic Leukemia. However, it does mention other treatments like bendamustine and rituximab, which have shown high response rates in relapsed or refractory cases. For example, bendamustine and rituximab have been effective in improving outcomes, and the combination of venetoclax and rituximab has shown better progression-free survival compared to bendamustine and rituximab. Without specific data on Nemtabrutinib, it's unclear how it compares to these treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Nemtabrutinib for Chronic Lymphocytic Leukemia?

The combination of bendamustine and rituximab has shown high response rates in relapsed/refractory chronic lymphocytic leukemia, and the addition of ibrutinib to this combination improved disease outcomes. Additionally, bendamustine and rituximab were found to be potentially less toxic compared to the standard therapy of fludarabine, cyclophosphamide, and rituximab. ^{1 2 3 4 5}

What safety data is available for Nemtabrutinib in treating Chronic Lymphocytic Leukemia?

The safety data for Nemtabrutinib, also known as MK-1026 or ARQ 531, specifically for Chronic Lymphocytic Leukemia (CLL), is not directly addressed in the provided research. However, safety data for related treatments like Bendamustine and Rituximab, which are often used in combination therapies for CLL, is available. Bendamustine has been associated with hematological events and gastrointestinal disturbances, with late onset neutropenia (LON) being a notable concern, especially in combination with Rituximab. The BRIGHT study indicates that Bendamustine plus Rituximab (BR) is noninferior to standard regimens but has higher incidences of vomiting and drug-hypersensitivity reactions. Close monitoring and prophylactic measures are recommended for managing LON in patients undergoing BR treatment. ^{6 7 8 9 10}

Is Nemtabrutinib safe for humans?

Bendamustine, often used with rituximab, has been studied for safety in treating conditions like chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Common side effects include blood-related issues and stomach problems, but it generally has a low risk of causing hair loss. Late onset neutropenia (a drop in white blood cells) is a concern, especially in certain patients, and requires careful monitoring. ^{6 7 8 9 10}

Is the drug Nemtabrutinib a promising treatment for Chronic Lymphocytic Leukemia?

Nemtabrutinib, when combined with other drugs like bendamustine and rituximab, shows promise in treating Chronic Lymphocytic Leukemia (CLL). These combinations have been effective in improving response rates and managing the disease, especially in patients who have relapsed or have not responded to previous treatments. ^{1 3 4 11 12}

What makes the drug Nemtabrutinib unique for treating chronic lymphocytic leukemia?

Nemtabrutinib is a novel drug being studied for chronic lymphocytic leukemia, and it is part of a combination treatment that includes several other drugs like bendamustine and rituximab. This combination aims to improve treatment outcomes by potentially offering a different mechanism of action and possibly reducing toxicity compared to standard therapies. ^{1 3 4 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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]

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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. England 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. [2018]

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

Systemic Exposure of Rituximab Increased by Ibrutinib: Pharmacokinetic Results and Modeling Based on the HELIOS Trial. [2021]

3. England 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. [2022]

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

Ofatumumab and bendamustine in previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. [2019]

5. United States 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. [2019]

6. United States 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. [2022]

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

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. [2015]

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

Description of late onset neutropenia in indolent lymphoma patients treated with bendamustine plus rituximab. [2018]

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

Bendamustine. [2018]

10. United States 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. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

[Chronic lymphocytic leukemia: current standards and novel approaches]. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Novel agents for chronic lymphocytic leukemia. [2021]