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Nemtabrutinib for Hematologic Malignancies

This study is testing a drug called nemtabrutinib (MK-1026) in people with certain blood cancers (hematologic malignancies), including Waldenström's macroglobulinemia, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. The main goals are to see how safe nemtabrutinib is and how well it works. Researchers will look for side effects and how many people experience them, as well as how many people need to stop treatment due to side effects. You may be able to join if you are 18 or older, have a good enough general health status (ECOG performance status of 0 to 2), and are expected to live at least 3 months. The study is currently unclear on its recruitment status and plans to enroll about 490 participants.

Study design
This is an interventional study with two parts: a dose escalation and confirmation part, followed by an expansion part with 8 disease-specific groups. The study plans to enroll about 490 participants.
What's involved
Not specified in the trial record.
Compensation
Not stated in the trial record.
Follow-up
Researchers will monitor participants for adverse events for up to about 71 months and for discontinuing treatment due to adverse events for up to about 42 months.

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NCT04728893

Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)

Recruiting
PHASE2Ages 18+InterventionalTreatment
Merck Sharp & Dohme LLC
~490 participants
Updated 2026-08-21 on ClinicalTrials.gov
What's tested:Nemtabrutinib

At a glance

Recruiting sites
95 of 121 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)
Measured over Up to ~56 days (Cycles 1-2, cycle = 28 days)
+5 more outcomes measured

Conditions

Hematologic Malignancies
Waldenstroms Macroglobulinaemia
Non-Hodgkins Lymphoma
Chronic Lymphocytic Leukaemia

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Chronic Lymphocytic LeukemiaFollicular LymphomaHematologic NeoplasmMantle Cell LymphomaMarginal Zone LymphomaRichter SyndromeSmall Lymphocytic LymphomaWaldenstrom MacroglobulinemiaCD4 Gene

Where it's being run

121 sites across 85 states
Italy8
Israel7
Spain4
Turkey (Türkiye)4
Argentina3
Brazil3
California2
New Jersey2

Study leadership

  • Medical Director · STUDY_DIRECTOR · Merck Sharp & Dohme LLC

Who to contact

Toll Free Number
[email protected]
1-888-577-8839
Email the study team

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Do you actually qualify for this trial?

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Eligibility criteria

Inclusion

Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before C1D1 (the first dose of study treatment)
Has a life expectancy of at least 3 months, based on the investigator assessment
Has the ability to swallow and retain oral medication
Participants who are Hepatitis B surface antigen (HBsAg)-positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
Has adequate organ function
Male participants agree to refrain from donating sperm and agree to either remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for at least the time required to eliminate the study intervention after last dose of study intervention
Female participants assigned female sex at birth who are not pregnant or breastfeeding are eligible to participate if not a participant of childbearing potential (POCBP), or if a POCBP they either use a contraceptive method that is highly effective OR remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle during the intervention period and for at least to eliminate study intervention after the last dose of study intervention
Participants with Human immunodeficiency virus (HIV) are eligible if they meet all of the following: the CD4 count is \>350 cells/uL at screening, the HIV viral load is below the detectable level, are on a stable ART regimen for at least 4 weeks prior to study entry, and are compliant with their ART
Has a confirmed diagnosis of Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) with
At least 2 lines of prior therapy (Part 1 only)
Part 2 Cohort A: CLL/SLL participants who are relapsed or refractory to prior therapy with a covalent, irreversible Bruton's tyrosine kinase inhibitor (BTKi), and a B-cell lymphoma 2 inhibitor (BCL2i). CLL participants must have received and failed, been intolerant to, or determined by their treating physician to be a poor phosphoinositide 3-kinase inhibitor (PI3Ki) candidate or ineligible for a PI3Ki per local guidelines
Part 2 Cohort B: CLL/SLL participants who are relapsed or refractory following at least 1 line of prior therapy and are BTKi treatment naive
Part 2 Cohort C: CLL/SLL participants with 17p deletion or tumor protein p53 (TP53) mutation who are relapsed or refractory following at least 1 line of prior therapy
Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i. NOTE: As of Protocol Amendment 09, at least 10 CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi, BCL2i and noncovalent/reversible BTKi (all three classes of therapies are required) will be enrolled into Cohort J
Has active disease for CLL/SLL clearly documented to initiate therapy
For SLL participants in Part 2: Has evaluable core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate at Screening (optional for participants enrolling in Part 1)
Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D)
Participants with pathologically confirmed Mantle-cell lymphoma (MCL), documented by either overexpression of cyclin D1 or t (11;14), who are relapsed or are refractory to chemoimmunotherapy and a covalent irreversible BTKi (Cohort E)
Participants with Marginal zone lymphoma (MZL) (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to at least one prior line of systemic therapy including an anti-CD20-based regimen
Participants with Follicular lymphoma (FL) who are relapsed or refractory to chemoimmunotherapy and immunomodulatory agents (such as lenalidomide based regimen) (Cohort G)
Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral Computed tomography (CT) scan
Has a lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate (Cohort D) at Screening
Has active disease defined as 1 of the following: systemic symptoms, physical findings, laboratory abnormalities, coexisting disease
Has measurable disease, satisfying any of the following: at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan (minimum measurement must be \>15 mm in the longest diameter or \>10 mm in the short axis); IgM ≥450 mg/dL; or bone marrow infiltration of 10%
Has fresh bone marrow aspirate or a lymph node biopsy for biomarker analysis at Screening or a lymph node biopsy from an archival

Exclusion

Has active HBV/HCV infection (Part 1 and Part 2)
Has a history of malignancy ≤3 years before providing documented informed consent. Participants with basal cell carcinoma of skin, squamous cell carcinoma of skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy are not excluded. Participants with low-risk, early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen \<10 ng/mL) either treated with definitive intent or untreated in active surveillance with SD are not excluded
Has active central nervous system (CNS) disease
Has an active infection requiring systemic therapy
Has received prior systemic anti-cancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before C1D1
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
Has any clinically significant gastrointestinal abnormalities that might alter absorption
History of severe bleeding disorders

What this trial measures

  • Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)Up to ~56 days (Cycles 1-2, cycle = 28 days)

    DLTs will be defined as toxicities observed during the first 2 cycles (8 weeks) of Part 1 and include: Grade ≥3 nonhematologic toxicity (except Grade 3 nausea, vomiting, diarrhea, rash, fatigue, and uncontrolled hypertension which will not be considered a DLT unless lasting ≥72 hours despite optimal supportive care); Grade 4 hematologic toxicity lasting \>7 days (except Grade 3 lymphocytosis, Grade 4 platelet count decreased of any duration, or Grade 3 platelet count decreased if associated with bleeding); any Grade 3 or Grade 4 nonhematologic laboratory abnormality if values result in drug-induced liver injury, or medical intervention is required, or the abnormality leads to hospitalization, or the abnormality persists for \>1 week (with exceptions); missing \>25% of nemtabrutinib doses as a result of drug-related adverse events (AEs) during the first 2 cycles (8 weeks); Grade 5 toxicity.

  • Part 1: Number of participants experiencing adverse events (AEs)Up to ~71 months

    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 1.

  • Part 1: Number of participants discontinuing study treatment due to AEsUp to ~42 months

    An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to an AE will be reported for Part 1.

  • Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)Up to ~61 months

    ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR). CR is defined as meeting the following criteria: no lymph nodes \>1.5 cm, spleen size \<13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10\^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10\^9/L or ≥50% increase from screening, hemoglobin \>11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow.

  • Part 2: ORR per Lugano criteria 2014 as assessed by ICRUp to ~61 months

    ORR per Lugano criteria 2014 is defined as the percentage of participants achieving a CR or PR. CR defined as EITHER CR by imaging (computed tomography \[CT\]): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR complete metabolic response (CMR): score of 1, 2 or 3 on the 5-point scale assessing fluorodeoxyglucose (FDG) metabolic activity in lymphomatous lesions (ranging from 1=no uptake above background to 5=uptake markedly higher than liver) AND bone marrow (BM) normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the sum of the product of diameters \[SPD\] of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR Partial Metabolic Response (PMR) with score of 4 or 5 on the FDG 5-point scale (with no new lesions) and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities.

  • Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICRUp to ~71 months

    ORR per IWWM criteria 2014 is defined as the percentage of participants achieving a CR, very good partial response (VGPR), or PR. CR is defined as all lymph nodes are normal in size (none ≥15 mm), liver and spleen normal in size, serum immunoglobulin M (IgM) values in the normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with a second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal), and ≥90% decrease from baseline in serum IgM, or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in serum IgM, and ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal).