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

NCT03162536 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: 1026-001ARQ 531-101MK-1026-001
• Study Type: interventional
• Target: 190
• Locations: 1 country
• Sites: 10

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.

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

Keywords

nemtabrutinib; Hematologic Malignancies; SLL; CLL; B-cell NHL; WM; BTK (Brutons tyrosine kinase); cancer; refractory; relapsed; Acalabrutinib; ArQule; BGB-3111; Blood Protein Disorders; Follicular Lymphoma; BTK Intolerant; C481; C481S; C481S Mutation; Cardiovascular Diseases; Chronic Lymphocytic Leukemia; DLBCL (Diffuse Large B-cell lymphoma); GS-4059; Hemorrhagic Disorders; Hemostatic Disorders; Ibrutinib; Immune System Diseases; Immunoproliferative Disorders; Leukemia; Leukemia, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphatic Diseases; Lymphoma; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Mantle Cell Lymphoma; Marginal zone lymphoma; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Plasma Cell; NHL (Non-Hodgkins Lymphoma); ONO-4059; Paraproteinemias; Small Lymphocytic Lymphoma; Tirabrutinib; Vascular Diseases; Waldenstrom Macroglobulinemia; Zanubrutinib

Outcome Measures

Primary Outcomes (5)

• Phase 1: Number of Participants Experiencing Dose Limiting Toxicity (DLT)

  DLT is defined by the occurrence of any of the following treatment emergent adverse event (TEAE) unless unequivocally due to the underlying malignancy or an extraneous cause within the first 28 days of study treatment (for dose escalation only) and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Any Grade 5 TEAE, any Grade 3 nonhematological TEAE except alopecia, nausea, vomiting, diarrhea, and transient Grade 3 laboratory abnormalities which recover within 1 week without intervention, any Grade 3 hematological TEAE that does not recover to Grade 1 or baseline within 7 days with the exception of Grade 3 lymphocytosis, which is considered to be an expected outcome of BTK inhibition, any Grade 4 nonhematological and hematological TEAE, or any other toxicity that in the view of the investigator represents a clinically significant hazard to the participant.

  Cycle 1 (up to 28 days)

• Phase 1: Number of Participants Who Experienced an Adverse Event (AE)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experienced an AE will be reported.

  Up to approximately 86 months

• Phase 1: Number of Participants Who Discontinued Study Treatment Due to an AE

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE will be reported.

  Up to approximately 86 months

• Phase 2: Expansion Cohorts A, B & C: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by the Investigator

  ORR is defined as the percentage of participants achieving a best overall response of complete response (CR), partial response (PR) or partial response with lymphocytosis (PRL). iwCLL criteria as assessed by the investigator. 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). 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.

  Up to approximately 64 months

• Phase 2: Expansion Cohorts A, B, C: ORR per Lugano Classification as Assessed by the Investigator

  ORR is defined as percentage of participants achieving best overall response of CR/PR per Lugano classification as assessed by investigator. CR defined as EITHER CR by imaging (computed tomography \[CT\]): all lymph nodes normal (none ≥15 mm) \& normal liver, spleen OR complete metabolic response (CMR): score of 1, 2 or3 on 5-point scale assessing fluorodeoxyglucose (FDG) metabolic activity in lymphomatous lesions (range: 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 sum of 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 4/5 on FDG 5-point scale (with no new lesions) \& decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities.

  Up to approximately 64 months

Secondary Outcomes (10)

• Phase 2: Number of Participants Who Experienced an AE

  Up to approximately 64 months

• Phase 2: Number of Participants Who Discontinued Study Treatment Due to an AE

  Up to approximately 64 months

• Time to Maximum Concentration (Tmax) of Nemtabrutinib

  Cycles 1-92: Days 1, 2: Predose and up to 16 hours postdose (each cycle length = 28 days, up to approximately 86 months)

• Maximum Concentration (Cmax) of Nemtabrutinib

  Cycles 1-92: Days 1, 2: Predose and up to 16 hours postdose (each cycle length = 28 days, up to approximately 86 months)

• Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24hrs)of Nemtabrutinib

  Cycles 1-92: Days 1, 2: Predose and up to 24 hours postdose (each cycle length = 28 days, up to approximately 86 months)

Study Arms (10)

Phase 1: Dose Escalation and Determination of RP2D

EXPERIMENTAL

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

Drug: Nemtabrutinib

Phase 2: Expansion Cohort A

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort B

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort C

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort D

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort E

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort F

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort G

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Cohort H

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Phase 2: Expansion Food Effect Cohort I

EXPERIMENTAL

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).

Drug: Nemtabrutinib

Interventions

Nemtabrutinib 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.

Also known as: ARQ 531, MK-1026

Phase 1: Dose Escalation and Determination of RP2D; Phase 2: Expansion Cohort A; Phase 2: Expansion Cohort B; Phase 2: Expansion Cohort C; Phase 2: Expansion Cohort D; Phase 2: Expansion Cohort E; Phase 2: Expansion Cohort F; Phase 2: Expansion Cohort G; Phase 2: Expansion Cohort H; Phase 2: Expansion Food Effect Cohort I

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (10)

Mayo Clinic Hospital ( Site 0140)

Scottsdale, Arizona, 85259, United States

Location

UCLA Hematology & Oncology ( Site 0017)

Los Angeles, California, 90095, United States

Location

Colorado Blood Cancer Institute ( Site 0225)

Denver, Colorado, 80218, United States

Location

University of Michigan ( Site 0018)

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic - Rochester ( Site 0138)

Rochester, Minnesota, 58905, United States

Location

Duke Cancer Center ( Site 0067)

Durham, North Carolina, 27710, United States

Location

The Ohio State University Wexner Medical Center ( Site 0056)

Columbus, Ohio, 43210, United States

Location

Tennessee Oncology, PLLC ( Site 0020)

Nashville, Tennessee, 37203, United States

Location

UT Southwestern Medical Center ( Site 0116)

Dallas, Texas, 75390-8562, United States

Location

University of Utah, Huntsman Cancer Institute ( Site 0122)

Salt Lake City, Utah, 84112, United States

Location

Related Publications (2)

• 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.

  PMID: 37930156 RESULT

• 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.

  PMID: 34398557 DERIVED

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Lymphoma, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Lymphoma, B-Cell, Marginal Zone; Hematologic Neoplasms; Neoplasms; Recurrence; Blood Protein Disorders; Cardiovascular Diseases; Dendritic Cell Sarcoma, Interdigitating; Hemorrhagic Disorders; Hemostatic Disorders; Immune System Diseases; Immunoproliferative Disorders; Leukemia; Leukemia, B-Cell; Leukemia, Lymphoid; Lymphatic Diseases; Lymphoma; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Neoplasms by Histologic Type; Neoplasms, Plasma Cell; Paraproteinemias; Vascular Diseases

Interventions

ARQ531

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Site; Histiocytic Disorders, Malignant; Histiocytosis

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single group assignment (definition : A type of intervention model describing a clinical trial in which all participants receive the same intervention/treatment.)

Study Record Dates

• First Submitted: May 15, 2017
• First Posted: May 22, 2017
• Study Start: June 26, 2017
• Primary Completion (Estimated): September 18, 2026
• Study Completion (Estimated): September 18, 2026
• Last Updated: September 8, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share

Locations

US (10)