Nemtabrutinib for Chronic Lymphocytic Leukemia

Recruiting at 184 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: P-gp substrates, CYP3A inducers

Disqualifiers: Active HBV/HCV, CNS involvement, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 104 months

1200 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to evaluate nemtabrutinib compared with investigator's choice of ibrutinib or acalabrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have not received any prior therapy. The primary hypotheses are that (1) nemtabrutinib is non-inferior to ibrutinib or acalabrutinib with respect to objective response rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 by blinded independent central review (BICR) and (2) nemtabrutinib is superior to ibrutinib or acalabrutinib with respect to progression free survival (PFS) per iwCLL Criteria 2018 by BICR.

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

The trial does not specify if you need to stop taking your current medications, but you cannot be on certain drugs like p-glycoprotein substrates with a narrow therapeutic index or strong/moderate CYP3A inducers or inhibitors.

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

Research shows that acalabrutinib, a component of the treatment, is effective for chronic lymphocytic leukemia (CLL) and is better tolerated than similar drugs like ibrutinib. It has a favorable safety profile without compromising effectiveness, making it a promising option for CLL treatment. ^{1 2 3 4 5}

What is the safety profile of acalabrutinib for chronic lymphocytic leukemia?

Acalabrutinib, a treatment for chronic lymphocytic leukemia, generally has a favorable safety profile compared to similar drugs like ibrutinib. It may cause some side effects such as headaches and cough, and there is a higher risk of neutropenia (low white blood cell count) when used with obinutuzumab. However, it tends to have fewer severe side effects like atrial fibrillation (irregular heartbeat) and hypertension (high blood pressure) compared to ibrutinib. ^{3 6 7 8 9}

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

Nemtabrutinib is unique because it is a novel Bruton tyrosine kinase inhibitor, similar to acalabrutinib and ibrutinib, which are known for their effectiveness in targeting specific pathways in chronic lymphocytic leukemia. This drug offers a new option for patients, potentially improving outcomes by providing an alternative mechanism of action compared to traditional chemotherapy. ^{1 5 10 11 12}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who need treatment and have not been treated before. They should be able to perform daily activities with ease to moderate difficulty (ECOG 0-2), swallow pills, and if they have hepatitis B or C, it must be under control. People with HIV can join if they meet all other criteria.

Inclusion Criteria

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

I am hepatitis B positive but have been on antiviral therapy for over 4 weeks with an undetectable HBV DNA level.

I had hepatitis C but my current tests show no virus.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either nemtabrutinib or investigator's choice of ibrutinib or acalabrutinib until disease progression or unacceptable toxicity

Up to 104 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 104 months

Treatment Details

Interventions

• Acalabrutinib
• Ibrutinib
• Nemtabrutinib

Trial Overview The study compares Nemtabrutinib against either Ibrutinib or Acalabrutinib in treating CLL/SLL patients without prior therapy. It aims to see if Nemtabrutinib works as well as the others in shrinking tumors and helps patients stay disease-free longer.

Participant Groups

Group I: Nemtabrutinib Experimental Treatment 1 Intervention

Participants will receive nemtabrutinib at specified dose until disease progression, unacceptable toxicity or until discontinuation criteria are met.

Group II: Ibrutinib/Acalabrutinib Active Control 2 Interventions

Participants will receive investigator's choice of ibrutinib or acalabrutinib at specified dose until disease progression, unacceptable toxicity or until discontinuation criteria are met.

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell 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 phase III study involving 310 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared to investigator's choice treatments, with a median PFS not reached for acalabrutinib versus 16.5 months for the comparator group.

Acalabrutinib demonstrated a favorable safety profile, with serious adverse events occurring in 29% of patients, compared to 56% for idelalisib plus rituximab and 26% for bendamustine plus rituximab, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Ghia, P., Pluta, A., Wach, M., et al.[2021]

In a phase III trial involving patients with previously treated chronic lymphocytic leukemia, acalabrutinib and ibrutinib showed equivalent progression-free survival rates, indicating similar efficacy in treatment.

Acalabrutinib was better tolerated by patients compared to ibrutinib, likely due to its greater selectivity, suggesting it may be a safer option for long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BTK Inhibitors Show Similar Benefits in CLL. [2022]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

A systematic review and network meta-analysis of 3 trials involving targeted agents for chronic lymphocytic leukemia found that acalabrutinib plus obinutuzumab (AO) significantly improves progression-free survival (PFS) compared to ibrutinib-obinutuzumab (IO) and venetoclax-obinutuzumab (VO).

No significant differences in adverse event frequency were observed among the different targeted agents, suggesting that AO is not only more effective but also maintains a similar safety profile compared to IO and VO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison Between Venetoclax-based and Bruton Tyrosine Kinase Inhibitor-based Therapy as Upfront Treatment of Chronic Lymphocytic Leukemia (CLL): A Systematic Review and Network Meta-analysis. Molica, S., Giannarelli, D., Montserrat, E.[2022]

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]

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, was found to increase the risk of any-grade cardiac events in patients with chronic lymphocytic leukemia, with a risk ratio of 1.75.

There was a notable trend indicating a higher risk of any-grade atrial fibrillation associated with acalabrutinib, with a risk ratio of 2.56, although no significant increase in hypertension or high-grade cardiac events was observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. Htut, TW., Han, MM., Thein, KZ.[2022]

In the ELEVATE-RR trial involving 529 patients with previously treated chronic lymphocytic leukemia, acalabrutinib demonstrated noninferior progression-free survival compared to ibrutinib while also showing a lower incidence of key adverse events (AEs).

Patients taking acalabrutinib experienced fewer common AEs, such as diarrhea and hypertension, compared to those on ibrutinib, leading to a lower rate of discontinuation due to AEs (hazard ratio of 0.62), indicating a better safety profile for acalabrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Seymour, JF., Byrd, JC., Ghia, P., et al.[2023]

Acalabrutinib, a selective BTK inhibitor, has shown excellent efficacy in treating chronic lymphocytic leukemia (CLL) with a favorable safety profile, making it a promising option for patients.

Unlike earlier BTK inhibitors, acalabrutinib minimizes off-target effects, which helps reduce side effects and the likelihood of treatment interruptions, enhancing patient tolerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib. Vitale, C., Gibbons, JL., Ferrajoli, A.[2022]

Acalabrutinib, a selective BTK inhibitor, was found to be effective in treating 73% of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were intolerant to ibrutinib, with a median follow-up of 35 months showing promising survival rates.

The most common side effects of acalabrutinib included diarrhea and headache, but it was generally well tolerated, making it a suitable alternative for patients who cannot continue with ibrutinib due to adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Rogers, KA., Thompson, PA., Allan, JN., et al.[2021]

Acalabrutinib monotherapy is likely to be cost-effective compared to chlorambucil plus obinutuzumab for treatment-naive chronic lymphocytic leukemia (CLL), with an incremental cost-effectiveness ratio (ICER) of $81,960 per quality-adjusted life-year (QALY) gained over a 30-year period.

The combination of acalabrutinib and obinutuzumab showed a higher ICER of $152,153/QALY, indicating that while both treatments are effective, acalabrutinib alone may offer a more favorable cost-benefit ratio in the US Medicare population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of acalabrutinib regimens in treatment-naïve chronic lymphocytic leukemia in the United States. Munir, T., Genovez, V., Genestier, V., et al.[2023]

In a phase 3 study involving 535 patients with treatment-naive chronic lymphocytic leukaemia, acalabrutinib combined with obinutuzumab or as a monotherapy significantly improved progression-free survival compared to the standard treatment of obinutuzumab with chlorambucil, with median survival not reached for the acalabrutinib groups versus 22.6 months for the chlorambucil group.

The safety profile of acalabrutinib was favorable, with fewer infusion reactions and a lower incidence of grade 3 or higher adverse events compared to the obinutuzumab-chlorambucil group, indicating it is a viable chemotherapy-free treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Sharman, JP., Egyed, M., Jurczak, W., et al.[2021]

Ibrutinib is a targeted therapy specifically designed for treating chronic lymphocytic leukemia (CLL), which is a type of cancer that affects the blood and bone marrow.

This novel treatment works by inhibiting Bruton's tyrosine kinase (BTK), a key enzyme that helps cancer cells survive and proliferate, leading to improved patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. Parmar, S., Patel, K., Pinilla-Ibarz, J.[2021]

References

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

ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. [2021]

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

BTK Inhibitors Show Similar Benefits in CLL. [2022]

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

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. [2021]

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

Comparison Between Venetoclax-based and Bruton Tyrosine Kinase Inhibitor-based Therapy as Upfront Treatment of Chronic Lymphocytic Leukemia (CLL): A Systematic Review and Network Meta-analysis. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

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

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

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials. [2022]

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

Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. [2023]

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

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib. [2022]

9. Italy pubmed.ncbi.nlm.nih.gov

Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of acalabrutinib regimens in treatment-naïve chronic lymphocytic leukemia in the United States. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. [2021]

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

Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia. [2021]