Recruiting
Phase 2

Nemtabrutinib

Sponsor:

Merck Sharp & Dohme LLC

Code:

NCT04728893

Conditions

Hematologic Malignancies

Waldenstroms Macroglobulinaemia

Non-Hodgkins Lymphoma

Chronic Lymphocytic Leukaemia

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Nemtabrutinib

Study Details

Brief summary:

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).

Conditions

Hematologic Malignancies

Waldenstroms Macroglobulinaemia

Non-Hodgkins Lymphoma

Chronic Lymphocytic Leukaemia

Study ID

NCT04728893

Start date

Apr 5, 2021

Status verified date

Aug, 2026

Completion date

Jan 4, 2029

Anticipated

Primary completion date

Jan 4, 2029

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • 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

Part 1 and Part 2 (Cohorts A to C and J)

  • 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)

Part 2 (Cohorts D to G)

\- Has a confirmed diagnosis of and meets the following prior therapy requirements:

  • 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

Part 2 (Cohort H): confirmed diagnosis of Waldenström's macroglobulinemia (WM); participants who are relapsed or refractory to standard therapies for WM including chemoimmunotherapy and a covalent irreversible BTKi

  • 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 Criteria:

  • 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

Study Design

Enrollment

490 participants

Anticipated

Intervention Model

Single group

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Nemtabrutinib

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

Interventions

Nemtabrutinib

Nemtabrutinib tablets administered orally QD.

Primary outcome measure

  • Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) [ Time Frame: Up to ~56 days (Cycles 1-2, cycle = 28 days) ]
  • Part 1: Number of participants experiencing adverse events (AEs) [ Time Frame: Up to ~71 months ]
  • Part 1: Number of participants discontinuing study treatment due to AEs [ Time Frame: Up to ~42 months ]
  • Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR) [ Time Frame: Up to ~61 months ]
  • Part 2: ORR per Lugano criteria 2014 as assessed by ICR [ Time Frame: Up to ~61 months ]
  • Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR [ Time Frame: Up to ~71 months ]

Central Contacts and Locations

Central contacts

Locations

Highlands Oncology Group ( Site 2728)

Recruiting

Springdale, Arkansas, United States, 72762

Contacts

Study Coordinator

479-872-8130

University of California San Diego Moores Cancer Center ( Site 2717)

Recruiting

La Jolla, California, United States, 92093-0698

Contacts

Study Coordinator

858-534-5201

Colorado Blood Cancer Institute ( Site 2726)

Recruiting

Denver, Colorado, United States, 80218

Contacts

Study Coordinator

720-754-4800

Astera Cancer Care ( Site 2732)

Recruiting

East Brunswick, New Jersey, United States, 08816

Contacts

Study Coordinator

732-672-6405

John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704)

Recruiting

Hackensack, New Jersey, United States, 07601

Contacts

Study Coordinator

551-996-3003

UT Southwestern-Harold C. Simmons Cancer Center ( Site 2730)

Recruiting

Dallas, Texas, United States, 75390

Contacts

Study Coordinator

972-695-9450

Medical Oncology Associates (Summit Cancer Centers) ( Site 2710)

Recruiting

Spokane, Washington, United States, 99208

Contacts

Study Coordinator

509-462-2273

Arthur J.E. Child Comprehensive Cancer Centre ( Site 0401)

Recruiting

Calgary, Alberta, Canada, T2N 5G2

Contacts

Study Coordinator

4035213723

The Ottawa Hospital ( Site 0404)

Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Contacts

Study Coordinator

613 737-7700

Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406)

Recruiting

Toronto, Ontario, Canada, M5G 2M9

Contacts

Study Coordinator

416-946-2827

CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0403)

Recruiting

Montreal, Quebec, Canada, H1T 2M4

Contacts

Study Coordinator

5142523400

Jewish General Hospital ( Site 0400)

Recruiting

Montreal, Quebec, Canada, H3T 1E2

Contacts

Study Coordinator

5143408222 x 24572

More Information

Sponsor

Merck Sharp & Dohme LLC

Last update posted

Aug 21, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by Merck Sharp & Dohme LLC on 2026-08-21.