A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)

NCT ID: NCT03162536

Last Updated: 2025-09-08

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 190 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-26
• Study Completion Date: 2026-09-18

Brief Summary

This study aims to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic (PK) of nemtabrutinib (formerly ARQ 531) tablets in selected participants with relapsed or refractory hematologic malignancies. No formal hypothesis testing will be performed for this study.

Detailed Description

This study includes 2 parts: Phase 1 (dose escalation) and Phase 2 (dose expansion). In Phase 1, participants will enroll using 3+3 dose escalation design. The starting dose of nemtabrutinib in oral tablet form was 5mg/day continuously. Dose escalation will continue until the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) and dosing schedule is reached based on protocol-defined dose limiting toxicity (DLT). After the determination of the RP2D, 9 expansion cohorts will be initiated to evaluate the safety, tolerability, and efficacy of nemtabrutinib at RP2D in participants with specifically defined disease.

Conditions

Lymphoma, B-Cell; Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia; Mantle Cell Lymphoma; Diffuse Large B Cell Lymphoma; Richter's Transformation; Follicular Lymphoma; Marginal Zone Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 1: Dose Escalation and Determination of RP2D

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

Group Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort A

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort B

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort C

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort D

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort E

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort F

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort G

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Cohort H

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Phase 2: Expansion Food Effect Cohort I

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 Type: EXPERIMENTAL

Nemtabrutinib

Intervention Type: DRUG

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Interventions

Nemtabrutinib

Nemtabrutinib will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg. For Expansion Food Effect Cohort I, nemtabrutinib will be orally administered once per day under fasted and non-fasted condition.

Intervention Type: DRUG

Other Intervention Names

ARQ 531; MK-1026

Eligibility Criteria

Inclusion Criteria

• Signed written informed consent granted prior to initiation of any study-specific procedures
• For the dose escalation cohorts, relapsed or refractory (R/R) participants with a diagnosis of B-cell Non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) and Waldenstrom macroglobulinemia (WM) who have received at least two prior systemic therapies . Participants must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Participants with low grade lymphoma must be progressing and requiring treatment
• For the expansion cohorts, the following criteria must be met:

• Cohort A: 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 Bruton's tyrosine kinase (BTK) mutation on C481 residue
• Cohort B: 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. In this study, intolerance to standard therapy is defined as having experienced a grade 3 or higher adverse event that was caused by the standard therapy and resulted in treatment discontinuation
• Cohort C: Richter's transformation (RT) participants who have failed at least one prior therapy
• Cohort D: Follicular Lymphoma (FL) participants who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A
• Cohort E: Mantle Cell Lymphoma (MCL) participants who have failed at least 2 prior systemic therapies
• Cohort F: Marginal Zone Lymphoma (MZL) participants who have failed at least 2 prior systemic therapies
• Cohort G: High-grade B-cell lymphoma participants who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations
• Cohort H: WM participants who have failed at least 2 prior systemic therapies
• Cohort I (Food Effect): relapsed or refractory participants with a diagnosis of B-cell NHL, CLL/SLL or WM who have received at least 2 prior systemic therapies, or 1 prior therapy for RT participants. Participants must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Participants with low grade lymphoma must be progressing and requiring treatment.
• Disease status requirement:

• For CLL participanst symptomatic disease that mandates treatment (Hallek et al. 2018)
• For B-cell NHL participants, measurable disease by imaging scan
• For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Good organ function
• Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection
• Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in participants with documented Gilbert's syndrome)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN
• Platelet count ≥ 50,000/µL
• Absolute neutrophil count (ANC) ≥ 1000/µL
• Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
• For men and women of child-bearing potential, willing to use adequate contraception (e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study
• Female participants of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing
• Ability to swallow oral medications without difficulty

Exclusion Criteria

• Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 5 half-lives or four weeks (whichever is shorter) prior to treatment initiation, or oral therapy within 5 half-lives or one week (whichever is shorter) prior to treatment initiation
• Transformation of follicular lymphoma (FL) to a more aggressive subtype of lymphoma or grade 3b FL
• Participants currently being treated with the following drugs:

• CYP2C8 substrates with a narrow therapeutic index (such as paclitaxel)
• P-gp substrates with a narrow therapeutic index (such as digoxin)
• CYP3A strong inducers (such as rifampin) Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment
• Active central nervous system (CNS) involvement
• Pregnant or breast-feeding women
• Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug
• Uncontrolled illness including but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in the past six months, and psychiatric illness that would limit compliance with study requirements
• QT corrected (QTc) prolongation (defined as a QTc > 450 msecs) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
• Active Hepatitis B or Hepatitis C infection.
• Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the participant's safety or interfere with the evaluation of the safety of the study agent
• History of prior cancer within < 1 year, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

Mayo Clinic Hospital ( Site 0140)

Scottsdale, Arizona, United States

UCLA Hematology & Oncology ( Site 0017)

Los Angeles, California, United States

Colorado Blood Cancer Institute ( Site 0225)

Denver, Colorado, United States

University of Michigan ( Site 0018)

Ann Arbor, Michigan, United States

Mayo Clinic - Rochester ( Site 0138)

Rochester, Minnesota, United States

Duke Cancer Center ( Site 0067)

Durham, North Carolina, United States

The Ohio State University Wexner Medical Center ( Site 0056)

Columbus, Ohio, United States

Tennessee Oncology, PLLC ( Site 0020)

Nashville, Tennessee, United States

UT Southwestern Medical Center ( Site 0116)

Dallas, Texas, United States

University of Utah, Huntsman Cancer Institute ( Site 0122)

Salt Lake City, Utah, United States

Countries

United States

References

Woyach JA, Stephens DM, Flinn IW, Bhat SA, Savage RE, Chai F, Eathiraj S, Reiff SD, Muhowski EM, Granlund L, Szuszkiewicz L, Wang W, Schwartz B, Ghori R, Farooqui MZH, Byrd JC. First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma. Cancer Discov. 2024 Jan 12;14(1):66-75. doi: 10.1158/2159-8290.CD-23-0670.

Reference Type: RESULT

PMID: 37930156 (View on PubMed)

Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.

Reference Type: DERIVED

PMID: 34398557 (View on PubMed)

Related Links

https://www.merckclinicaltrials.com/

Merck Clinical Trials Information

Other Identifiers

ARQ 531-101

Identifier Type: OTHER

Identifier Source: secondary_id

MK-1026-001

Identifier Type: OTHER

Identifier Source: secondary_id

1026-001

Identifier Type: -

Identifier Source: org_study_id