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

Primary Purpose

Lymphoma, B-Cell, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Nemtabrutinib

About this trial

This is an interventional treatment trial for Lymphoma, B-Cell focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Each prospective participant must meet ALL of the following inclusion criteria in order to be eligible for this study:

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
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

Potential participants who meet ANY of the following exclusion criteria are not eligible for enrollment into this study:

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:
- cytochrome P 450 (CYP) 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin)
- CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel)
- CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin)
- CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide)
- P-gp substrates with a narrow therapeutic index (such as digoxin) 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
Prior allogeneic bone marrow transplant
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). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.
Active human immunodeficiency virus (HIV) infection, 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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm Type

Experimental

Arm Label

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

Arm Description

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

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).

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).

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).

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).

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).

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).

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).

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).

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).

Outcomes

Primary Outcome Measures

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.

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.

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

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.

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.

Secondary Outcome Measures

Phase 2: Number of Participants Who Experienced an AE

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

Time to Maximum Concentration (Tmax) of Nemtabrutinib

Blood samples will be collected at prespecified time points to determine Tmax of nemtabrutinib.

Maximum Concentration (Cmax) of Nemtabrutinib

Blood samples will be collected at prespecified time points to determine Cmax of nemtabrutinib.

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

Blood samples will be collected at prespecified time points to determine AUC 0-24hrs of nemtabrutinib.

Terminal Elimination Half-Life (t1/2) of Nemtabrutinib

t1/2 is the time it takes for the concentration of nemtabrutinib in the body to decrease by half during the elimination phase.

Phase 2: Expansion Cohorts D-H: ORR per iwCLL Criteria as Assessed by the Investigator

Phase 2: Expansion Cohorts D-H: ORR per Lugano classification as Assessed by the Investigator

Phase 2: Expansion Cohorts A, B, H: Duration of Response (DOR) per iwCLL Criteria as Assessed by the Investigator

DOR is defined as the time from the first documented evidence of CR or PR (or PRL for CLL/SLL participants) until progressive disease or death due to any cause, whichever occurs first. 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.

Phase 2: Expansion Cohorts C-G: DOR per Laguna Classification As Assessed by Investiigator

DOR is defined as time from first documented evidence of CR/PR (or PRL for CLL/SLL participants) until progressive disease or death due to any cause, whichever occurs first. 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 FDG metabolic activity in lymphomatous lesions (range: 1=no uptake above background to 5=uptake markedly higher than liver) AND BM normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in SPD of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR 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.

Full Information

NCT ID

NCT03162536

First Posted

May 15, 2017

Last Updated

September 20, 2023

Sponsor

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

1. Study Identification

Unique Protocol Identification Number

NCT03162536

Brief Title

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

Official Title

A Phase 1/2 Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ARQ 531 in Selected Subjects With Relapsed or Refractory Hematologic Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

June 26, 2017 (Actual)

Primary Completion Date

September 13, 2024 (Anticipated)

Study Completion Date

September 13, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

190 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Phase 1: Dose Escalation and Determination of RP2D

Arm Type

Experimental

Arm Description

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

Arm Title

Phase 2: Expansion Cohort A

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort B

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort C

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort D

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort E

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort F

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort G

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Cohort H

Arm Type

Experimental

Arm Description

Arm Title

Phase 2: Expansion Food Effect Cohort I

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Nemtabrutinib

Other Intervention Name(s)

ARQ 531, MK-1026

Intervention Description

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.

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Cycle 1 (up to 28 days)

Title

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

Description

Time Frame

Up to approximately 86 months

Title

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

Description

Time Frame

Up to approximately 86 months

Title

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

Description

Time Frame

Up to approximately 64 months

Title

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

Description

Time Frame

Up to approximately 64 months

Secondary Outcome Measure Information:

Title

Phase 2: Number of Participants Who Experienced an AE

Description

Time Frame

Up to approximately 64 months

Title

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

Description

Time Frame

Up to approximately 64 months

Title

Time to Maximum Concentration (Tmax) of Nemtabrutinib

Description

Blood samples will be collected at prespecified time points to determine Tmax of nemtabrutinib.

Time Frame

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

Title

Maximum Concentration (Cmax) of Nemtabrutinib

Description

Blood samples will be collected at prespecified time points to determine Cmax of nemtabrutinib.

Time Frame

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

Title

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

Description

Blood samples will be collected at prespecified time points to determine AUC 0-24hrs of nemtabrutinib.

Time Frame

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

Title

Terminal Elimination Half-Life (t1/2) of Nemtabrutinib

Description

t1/2 is the time it takes for the concentration of nemtabrutinib in the body to decrease by half during the elimination phase.

Time Frame

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

Title

Phase 2: Expansion Cohorts D-H: ORR per iwCLL Criteria as Assessed by the Investigator

Description

Time Frame

Up to approximately 64 months

Title

Phase 2: Expansion Cohorts D-H: ORR per Lugano classification as Assessed by the Investigator

Description

Time Frame

Up to approximately 64 months

Title

Phase 2: Expansion Cohorts A, B, H: Duration of Response (DOR) per iwCLL Criteria as Assessed by the Investigator

Description

Time Frame

Up to approximately 64 months

Title

Phase 2: Expansion Cohorts C-G: DOR per Laguna Classification As Assessed by Investiigator

Description

Time Frame

Up to approximately 64 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Each prospective participant must meet ALL of the following inclusion criteria in order to be eligible for this study: 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 Potential participants who meet ANY of the following exclusion criteria are not eligible for enrollment into this study: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Merck Sharp & Dohme LLC

Official's Role

Study Director

Facility Information:

Facility Name

Mayo Clinic Hospital ( Site 0140)

City

Scottsdale

State/Province

Arizona

ZIP/Postal Code

85259

Country

United States

Facility Name

UCLA Hematology & Oncology ( Site 0017)

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Facility Name

Colorado Blood Cancer Institute ( Site 0225)

City

Denver

State/Province

Colorado

ZIP/Postal Code

80218

Country

United States

Facility Name

University of Michigan ( Site 0018)

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Mayo Clinic - Rochester ( Site 0138)

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

58905

Country

United States

Facility Name

Duke Cancer Center ( Site 0067)

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

The Ohio State University Wexner Medical Center ( Site 0056)

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

Tennessee Oncology, PLLC ( Site 0020)

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37203

Country

United States

Facility Name

UT Southwestern Medical Center ( Site 0116)

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390-8562

Country

United States

Facility Name

University of Utah, Huntsman Cancer Institute ( Site 0122)

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84112

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

IPD Sharing URL

http://engagezone.msd.com/ds_documentation.php

Citations:

PubMed Identifier

34398557

Citation

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.

Results Reference

derived

Links:

URL

https://www.merckclinicaltrials.com/

Description

Merck Clinical Trials Information

Learn more about this trial

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

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

Lymphoma, B-Cell, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial