Nemtabrutinib for Liver Disease

Recruiting at 2 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Merck Sharp & Dohme LLC

Must not be taking: HIV protease inhibitors

Disqualifiers: Cancer, Allergies, Drug abuse, others

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

Compensation: Varies

Number of Visits: 1

Duration: 1 day

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called nemtabrutinib (also known as MK-1026 or ARQ 531) to assess its movement through the body and its safety, especially in individuals with moderate liver problems. The trial includes two groups: one with liver impairment and another with healthy participants. It suits those with stable liver issues for over six months who haven't experienced recent liver-related health declines. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that participants with moderate hepatic impairment must have been on a stable medication regimen for at least 1 month and may need to stop certain medications for a specific period. Healthy control participants must refrain from using any medications, including prescription, nonprescription, and herbal remedies.

Is there any evidence suggesting that nemtabrutinib is likely to be safe for humans?

Research has shown that nemtabrutinib has been tested in various studies for different conditions. Results suggest it generally has a manageable safety profile. In studies involving patients with blood cancers like chronic lymphocytic leukemia (CLL), nemtabrutinib was well-tolerated. Some participants reported side effects, but these were usually mild to moderate.

The current trial tests nemtabrutinib in people with moderate liver disease, focusing on safety and the drug's movement through the body. Earlier research provides some reassurance about its safety. However, as this trial is in the early stages, gathering more detailed safety information remains a priority. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for liver disease, which often include medications like antivirals, immunosuppressants, or lifestyle changes, nemtabrutinib is a novel approach targeting a specific protein involved in the disease process. Researchers are excited about nemtabrutinib because it works by inhibiting Bruton's tyrosine kinase (BTK), a key player in inflammatory pathways, which could potentially reduce liver inflammation more effectively. This targeted mechanism could lead to better outcomes with fewer side effects compared to broader treatments. Additionally, its oral administration offers a convenient alternative to injections or infusions, making it more accessible for patients.

What evidence suggests that nemtabrutinib might be an effective treatment for liver disease?

This trial will evaluate nemtabrutinib, also known as MK-1026, for liver disease. Research has shown that nemtabrutinib is primarily being developed to treat blood cancers, where it effectively targets certain proteins that aid cancer cell growth. By blocking these proteins, nemtabrutinib may help prevent cancer cells from multiplying. Although information on its use for liver disease is limited, the drug's mechanism suggests potential benefits. Early findings in other conditions have shown it to be safe and promising, but further research is needed to confirm these results for liver disease. Participants in this trial will receive a single oral dose of 25 mg nemtabrutinib, either as part of Panel A for those with moderate hepatic impairment or as part of Panel B for healthy controls. ^{1 3 4 6 7}

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 a BMI of 18.0-40.0 who have chronic, stable moderate liver disease (Class B) and are not pregnant or breastfeeding. Participants must be in good general health, agree to use contraception, and provide informed consent.

Inclusion Criteria

I agree to use birth control.

I have signed the consent form for this study.

I am not pregnant or breastfeeding and cannot become pregnant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single oral dose of 25 mg nemtabrutinib

1 day

1 visit (in-person)

Pharmacokinetic Monitoring

Plasma pharmacokinetics of nemtabrutinib are measured at multiple time points postdose

2 weeks

Multiple visits (in-person) for blood sampling

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 days

What Are the Treatments Tested in This Trial?

Interventions

• Nemtabrutinib

Trial Overview The study tests Nemtabrutinib's effects on participants with moderate liver impairment compared to healthy individuals by measuring drug levels in the blood after a single dose and assessing safety and tolerability.

How Is the Trial Designed?

Group I: Panel B Experimental Treatment 1 Intervention

Healthy control participants will receive a single oral dose of 25 mg nemtabrutinib on Day 1.

Group II: Panel A Experimental Treatment 1 Intervention

Participants with moderate hepatic impairment will receive a single oral dose of 25 mg nemtabrutinib on Day 1.

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

Ibrutinib, a first-in-class Bruton's tyrosine kinase inhibitor, is used to treat various B-cell lymphoid malignancies, but its association with chronic hepatitis E virus infections is not well documented.

In a single-center study involving 4 cases of chronic hepatitis E in patients treated with ibrutinib, management with ribavirin was implemented, highlighting a potential treatment approach for this complication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribavirin for Chronic Hepatitis E Virus Infection in Ibrutinib-Exposed Patients. Protin, C., Abravanel, F., Alric, L., et al.[2023]

ARQ 197 is a novel, selective inhibitor of the c-MET receptor that has shown a favorable safety profile and predictable pharmacokinetics in Phase I studies, making it a promising candidate for combination therapies in cancer treatment.

In a global Phase II trial, ARQ 197 combined with erlotinib significantly improved progression-free and overall survival in patients with advanced non-small cell lung cancer, particularly benefiting those with non-squamous histologies and KRAS mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers. Adjei, AA., Schwartz, B., Garmey, E.[2021]

In a phase 3 study involving 340 patients with MET-high advanced hepatocellular carcinoma, tivantinib did not show a significant improvement in overall survival compared to placebo, with median survival times of 8.4 months for tivantinib and 9.1 months for placebo.

The study revealed that treatment with tivantinib resulted in a similar rate of grade 3 or worse adverse events compared to placebo, indicating that while tivantinib was not effective, it also did not lead to a higher incidence of severe side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Rimassa, L., Assenat, E., Peck-Radosavljevic, M., et al.[2022]

The combination of erlotinib and tivantinib showed a median progression-free survival (PFS) of 3.8 months compared to 2.3 months for erlotinib plus placebo, suggesting a potential benefit, particularly for patients with KRAS mutations who had a significantly improved PFS.

The treatment was well-tolerated with no significant differences in adverse events between the two groups, indicating that the combination therapy is safe for patients with advanced non-small-cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. Sequist, LV., von Pawel, J., Garmey, EG., et al.[2022]

In a study of 45 Japanese patients with EGFR mutation-positive non-small-cell lung cancer who had developed resistance to EGFR-TKIs, the combination of the c-Met inhibitor tivantinib and the EGFR-TKI erlotinib showed a low overall response rate of 6.7%, indicating limited efficacy in reversing resistance.

However, patients with high levels of c-Met experienced longer progression-free survival (4.1 months) and overall survival (20.7 months), suggesting that activated HGF/c-Met signaling may identify a subgroup of patients who could benefit from this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib. Azuma, K., Hirashima, T., Yamamoto, N., et al.[2021]

Fruquintinib significantly improved overall survival (OS) and progression-free survival (PFS) in Chinese patients with metastatic colorectal cancer and liver metastasis, with median OS of 8.61 months compared to 5.98 months for placebo, and median PFS of 3.71 months compared to 1.84 months for placebo.

The treatment showed a low incidence of hepatotoxicity, with only 3.8% of patients experiencing liver-related side effects, which is comparable to the 2.0% in the placebo group, indicating that fruquintinib is a safe option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subgroup Analysis by Liver Metastasis in the FRESCO Trial Comparing Fruquintinib versus Placebo Plus Best Supportive Care in Chinese Patients with Metastatic Colorectal Cancer. Qin, S., Xu, RH., Shen, L., et al.[2022]

In a study of 7 advanced non-small cell lung cancer (NSCLC) patients who previously experienced severe liver damage from gefitinib, switching to erlotinib resulted in no severe hepatotoxicity, indicating a safer alternative.

All patients maintained their treatment response after switching to erlotinib, achieving an impressive median progression-free survival of 372 days, demonstrating the efficacy of erlotinib in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erlotinib is a well-tolerated alternate treatment for non-small cell lung cancer in cases of gefitinib-induced hepatotoxicity. Yonesaka, K., Suzumura, T., Tsukuda, H., et al.[2018]

In a phase 1 study involving 31 participants, capmatinib's pharmacokinetics were not significantly affected by mild to moderate hepatic impairment, indicating that patients with these conditions can safely use the drug.

Interestingly, participants with severe hepatic impairment showed a 24% increase in drug exposure, but overall, the study found no new safety concerns associated with capmatinib use across different levels of liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of capmatinib in participants with hepatic impairment: A phase 1, open-label, single-dose, parallel-group study. Chen, X., Cui, X., Pognan, N., et al.[2022]

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. trialx.com trialx.com/clinical-trials/listings/306647/a-study-of-nemtabrutinib-in-participants-with-moderate-hepatic-impairment-mk-1026-015/

A Study of Nemtabrutinib in Participants With Moderate ... The purpose of this study is to compare the plasma pharmacokinetics (PK) of nemabrutinib (MK-1026) following a single oral dose of nemtabrutinib ...

3. 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.

4. clinicaltrials.eu clinicaltrials.eu/inn/nemtabrutinib/

Nemtabrutinib – Application in Therapy and Current ... Nemtabrutinib, also known as MK-1026 or ARQ 531, is a new medication being developed to treat various types of blood cancers.

5. app.trialscreen.org app.trialscreen.org/trials/phase-1-nemtabrutinib-participants-moderate-hepatic-impairment-mk-1026-trial-nct06442436

A Phase 1 study of nemtabrutinib in hepatic impairment A study evaluating the effects of moderate liver impairment on a new drug called nemtabrutinib · Study Goals · Study Design · Benefits: · Risks: · Interested in ...

6. ctv.veeva.com ctv.veeva.com/study/a-study-of-nemtabrutinib-in-participants-with-moderate-hepatic-impairment-mk1026015

A Study of Nemtabrutinib in Participants With Moderate ... The purpose of this study is to compare the plasma pharmacokinetics (PK) of nemabrutinib (MK-1026) following a single oral dose of ...

7. 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.