Nemtabrutinib for Blood Cancers

Recruiting at 117 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Merck Sharp & Dohme Corp.

Disqualifiers: Active infection, CNS disease, 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: Unknown

490 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), Richter's transformation, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia (WM).

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received prior systemic anti-cancer therapy within 4 weeks before starting the trial.

What data supports the effectiveness of the drug Nemtabrutinib for blood cancers?

The research on ibrutinib, a similar drug that targets Bruton's tyrosine kinase, shows clinical benefits in B-cell malignancies, suggesting that Nemtabrutinib, which may have a similar mechanism, could also be effective for blood cancers. ^{1 2 3 4 5}

What makes the drug Nemtabrutinib unique for treating blood cancers?

Nemtabrutinib (ARQ 531) is unique because it is a multi-kinase inhibitor that disrupts several signaling pathways crucial for cancer cell survival, unlike other treatments that target only one pathway. This broad action makes it effective in various genetic backgrounds and against resistant cancer cells, offering a promising option for blood cancers like acute myeloid leukemia. ^{6 7 8 9 10}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

This trial is for adults with certain blood cancers like CLL, SLL, Richter's transformation, MZL, MCL, FL, and WM. They must have tried at least two prior therapies (for some conditions), be able to take oral meds, not be pregnant or breastfeeding if female and agree to use contraception if male. People can't join if they've had recent cancer treatments or investigational drugs within the last month or have severe gastrointestinal issues that affect medication absorption.

Inclusion Criteria

I can care for myself and am up and about more than half of my waking hours.

I had Hepatitis C but my viral load is now undetectable.

You have had a recent bone marrow or lymph node biopsy for testing.

Exclusion Criteria

I have stomach or intestine problems that could affect how my body absorbs medicine.

You have a current Hepatitis B or Hepatitis C infection.

I have an active brain or spinal cord disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation and Confirmation

Participants receive nemtabrutinib to determine the recommended phase 2 dose (RP2D)

Up to 8 weeks

Multiple visits for dose escalation and monitoring

Cohort Expansion

Participants are assigned to disease-specific expansion cohorts to evaluate efficacy and safety

Up to 71 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 61 months

Treatment Details

Interventions

• Nemtabrutinib

Trial Overview The trial tests Nemtabrutinib's effectiveness and safety in treating various hematologic malignancies. Participants will receive this oral medication to see how well it works against their specific type of blood cancer and what its impact is on their overall health status.

Participant Groups

Group I: Nemtabrutinib Experimental Treatment 1 Intervention

Participants receive nemtabrutinib orally once daily (QD) until progressive disease (PD) or discontinuation.

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

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

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

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

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

Nilotinib, a second-generation tyrosine kinase inhibitor, has shown a 30-40-fold increase in effectiveness against the BCR-ABL1 oncoprotein linked to chronic myeloid leukemia, making it a strong option for patients who do not respond to imatinib.

In clinical trials, nilotinib demonstrated superior rates of major molecular responses in newly diagnosed patients compared to imatinib, leading to its accelerated approval by the FDA for first-line treatment in chronic phase chronic myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nilotinib: evaluation and analysis of its role in chronic myeloid leukemia. Garland, P., Apperley, J.[2022]

Dysregulation of protein phosphorylation, particularly on tyrosine residues, is a key factor in the development of blood cancers, highlighting the importance of targeting these pathways for treatment.

Next-generation ABL kinase inhibitors have transformed the treatment landscape for chronic myeloid leukemia (CML), while various kinase inhibitors targeting FLT3, BTK, and aurora-A are currently being evaluated in clinical trials for acute myeloid leukemia (AML) and lymphoid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Kinase inhibitors against hematological malignancies]. Tojo, A.[2018]

Ponatinib is a potent multitargeted kinase inhibitor that effectively inhibits both native and mutant BCR-ABL, as well as other kinases involved in hematologic cancers, showing IC50 values between 0.3 to 20 nmol/L.

In particular, ponatinib demonstrated strong efficacy against FLT3-ITD mutant acute myeloid leukemia (AML) cells, inducing apoptosis at concentrations below 10 nmol/L and leading to tumor regression in mouse models, suggesting its potential for treating FLT3-ITD-driven AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Gozgit, JM., Wong, MJ., Wardwell, S., et al.[2021]

Protein kinases are key targets for drug discovery in treating hematological malignancies, with established targets like BCR-ABL and FLT3, and emerging targets such as KDR and JAK2 fusion proteins.

The number of kinase-targeted therapies in clinical development has significantly increased over the past five years, highlighting the growing interest in these novel interventions for various blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinases as drug discovery targets in hematologic malignancies. Hannah, AL.[2019]

In a study of 1505 patients with chronic lymphocytic leukemia and mantle cell lymphoma, the incidence of atrial fibrillation (AF) in those treated with ibrutinib was 6.5% at 16.6 months, significantly higher than the 1.6% incidence in comparator groups.

Despite the increased risk of AF, most patients (85.7%) continued ibrutinib treatment, and serious bleeding events were rare, suggesting that AF can be effectively managed without needing to stop the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Brown, JR., Moslehi, J., O'Brien, S., et al.[2021]

ARQ 531, a multi-kinase inhibitor, shows promising anti-proliferative effects against acute myeloid leukemia (AML) cells in vitro, regardless of FLT3 ITD mutation status, by inhibiting key oncogenic kinases like SFK and BTK.

In pre-clinical models, ARQ 531 demonstrated modest in vivo activity and potential synergy with venetoclax, suggesting it could be an effective treatment option for AML when used in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia. Elgamal, OA., Mehmood, A., Jeon, JY., et al.[2021]

ARQ531, a new multiple kinase inhibitor, effectively disrupts cancer cell survival and progression in acute myeloid leukemia by targeting Bruton's tyrosine kinase and causing degradation of key proteins involved in tumor growth.

In preclinical models, ARQ531 demonstrated significant anti-tumor effects and was well-tolerated in a patient-derived leukemia mouse model, supporting its potential for clinical development as a targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs. Soncini, D., Orecchioni, S., Ruberti, S., et al.[2023]

Sorafenib effectively inhibits certain mutant receptor tyrosine kinases (PDGFRbeta and FLT3) associated with myeloid malignancies, showing potential as a treatment option for these conditions.

The drug induced cell cycle arrest and apoptosis in specific acute myeloid leukemia cell lines with FLT3 mutations, but was ineffective against the imatinib-resistant KIT(D816V) mutant, indicating a need for further clinical studies to explore its efficacy in myeloid cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Lierman, E., Lahortiga, I., Van Miegroet, H., et al.[2019]

In a study using immunocompromised mice with TCF3-PBX1 positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL), treatment with the BTK inhibitor ibrutinib did not extend the lifespan of the mice compared to those receiving a placebo, indicating limited efficacy in this context.

While ibrutinib was shown to be biologically active by reducing phospho-BTK levels, it did not improve leukemic cell viability or tumor growth, and it exhibited an antagonistic effect when combined with vincristine, suggesting it may not be the best treatment option for this specific type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib is not an effective drug in primografts of TCF3-PBX1. van de Ven, C., Boeree, A., Stalpers, F., et al.[2021]

Ibrutinib is the first FDA-approved drug that inhibits Burton's tyrosine kinase (BTK), effectively reducing B-cell proliferation and promoting apoptosis, making it a significant treatment for relapsed chronic lymphocytic leukemia and Waldenström's macroglobulinemia.

Despite its efficacy, ibrutinib can lead to serious side effects, including rare but severe hemorrhagic events, as demonstrated by a case of back pain caused by iliopsoas muscle hemorrhage in a patient after starting the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. Sarcon, A., Botta, GP., Patel, N., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Nilotinib: evaluation and analysis of its role in chronic myeloid leukemia. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

[Kinase inhibitors against hematological malignancies]. [2018]

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

Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Kinases as drug discovery targets in hematologic malignancies. [2019]

5. Italy pubmed.ncbi.nlm.nih.gov

Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Preclinical efficacy for a novel tyrosine kinase inhibitor, ArQule 531 against acute myeloid leukemia. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

The new small tyrosine kinase inhibitor ARQ531 targets acute myeloid leukemia cells by disrupting multiple tumor-addicted programs. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. [2019]

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

Ibrutinib is not an effective drug in primografts of TCF3-PBX1. [2021]

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

Spontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics): Brief Report. [2018]