Nemtabrutinib for Blood Cancers

Recruiting at 9 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

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

Compensation: Varies

Number of Visits: Unknown

190 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new pill called nemtabrutinib for patients with blood cancers that have returned or didn't respond to other treatments. The goal is to find a safe and effective dose of the drug. Nemtabrutinib is a new drug being tested for blood cancers, designed to reduce adverse effects.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for some drugs, such as CYP2C8 substrates, P-gp substrates, and CYP3A strong inducers. If you are taking these medications, you will need to stop them for a period before joining the study. For other medications, the protocol does not specify, so it's best to discuss with the study team.

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

The research mentions that ibrutinib, a similar drug to Nemtabrutinib, has shown clinical benefits in treating B-cell malignancies, which are a type of blood cancer. This suggests that drugs targeting similar pathways, like Nemtabrutinib, may also be effective in treating blood cancers. ^{1 2 3 4 5}

What makes the drug Nemtabrutinib unique for blood cancers?

Nemtabrutinib (ARQ 531) is unique because it is a multi-kinase inhibitor that targets multiple signaling pathways involved in cancer cell growth, unlike other treatments that may focus on a single pathway. This broad inhibition can lead to more effective disruption of cancer cell survival and proliferation, making it a promising option for treating blood cancers. ^{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 lymphoma and leukemia that have come back or didn't respond to treatment. They must have tried at least two other treatments, be able to take pills, and not be eligible for standard therapies. Pregnant women, those with serious health issues, recent heart attacks, active infections or a history of cancer within the last year (with some exceptions) can't join.

Inclusion Criteria

Signed written informed consent granted prior to initiation of any study-specific procedures

I can take care of myself and am up and about more than half of the day.

I have B-cell lymphoma or leukemia and standard treatments haven’t worked for me.

Exclusion Criteria

I am currently taking specific medications as listed.

Pregnant or breast-feeding women

I have other serious health issues that could make the study drug unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Participants receive multiple dose levels of nemtabrutinib to evaluate safety and determine the recommended Phase 2 dose (RP2D)

Up to approximately 22 months

Phase 2: Dose Expansion

Participants receive nemtabrutinib at the RP2D in various expansion cohorts to evaluate safety, tolerability, and efficacy

Up to approximately 64 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Nemtabrutinib

Trial Overview The study tests Nemtabrutinib tablets in patients with relapsed or refractory hematologic malignancies. It looks at how safe and tolerable the drug is, as well as its effects on the body and how it's processed by measuring various parameters over time without comparing it to another treatment.

Participant Groups

Group I: Phase 2: Expansion Food Effect Cohort I Experimental Treatment 1 Intervention

B-cell Non-Hodgkin's lymphoma (NHL), CLL/SLL and WM participants receive up to 65 mg of nemtabrutinib fasted (1 hour prior to or 2 hours after meal) and non-fasted per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group II: Phase 2: Expansion Cohort H Experimental Treatment 1 Intervention

Waldenström macroglobulinemia (WM) participants who have failed at least 2 prior systemic therapies receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group III: Phase 2: Expansion Cohort G Experimental Treatment 1 Intervention

High-grade B-cell lymphoma (BCL) participants who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations confirmed by flourescence in situ hybridization (FISH) or overexpression by immunohistochemistry (IHC) receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group IV: Phase 2: Expansion Cohort F Experimental Treatment 1 Intervention

Marginal Zone Lymphoma (MZL) participants who have failed at least 2 prior systemic therapies receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group V: Phase 2: Expansion Cohort E Experimental Treatment 1 Intervention

Mantle Cell Lymphoma (MCL) participants who have failed at least 2 prior systemic therapies receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group VI: Phase 2: Expansion Cohort D Experimental Treatment 1 Intervention

Follicular Lymphoma (FL) participants who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group VII: Phase 2: Expansion Cohort C Experimental Treatment 1 Intervention

Richter's transformation (RT) participants who have failed at least one prior therapy receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group VIII: Phase 2: Expansion Cohort B Experimental Treatment 1 Intervention

R/R CLL/SLL participants who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until PD, unacceptable AEs, or discontinuation at investigator's discretion (up to approximately 64 months).

Group IX: Phase 2: Expansion Cohort A Experimental Treatment 1 Intervention

Relapsed/Refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL) participants with at least 2 prior systemic therapies and previously treated with a covalent Bruton's tyrosine kinase inhibitor (BTKi) who must have a documented BTK mutation on C481 residue receive up to 65 mg of nemtabrutinib per day orally in each cycle (Cycle length = 28 days) until progressive disease (PD), unacceptable adverse events (AEs), or discontinuation at investigator's discretion (up to approximately 64 months).

Group X: Phase 1: Dose Escalation and Determination of RP2D Experimental Treatment 1 Intervention

Phase I: Dose Escalation and determination of RP2D, multiple dose levels of nemtabrutinib to be evaluated (Up to approximately 22 months).

Who Is Running the Clinical Trial?

ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Lead Sponsor

Trials

37

Recruited

3,600+

ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Lead Sponsor

Trials

37

Recruited

3,600+

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]

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]

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]

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]

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]

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]

References

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

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

2. Italy pubmed.ncbi.nlm.nih.gov

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

3. Japan pubmed.ncbi.nlm.nih.gov

[Kinase inhibitors against hematological malignancies]. [2018]

4. 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]

5. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

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

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

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