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Acalabrutinib

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Tyrosine Kinase Inhibitors

Ibrutinib

Tyrosine

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).

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.

Nemtabrutinib

Medical Director

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.

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.

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

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

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

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

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.

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.

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.

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.

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.

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

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

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

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)	NCT03162536	Lymphoma, B-Cel... Small Lymphocyt... Chronic Lymphoc... Waldenstrom Mac... Mantle Cell Lym... Diffuse Large B... Richter's Trans... Follicular Lymp... Marginal Zone L...	Nemtabrutinib	18 Years -	ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)	NCT03162536	Lymphoma, B-Cel... Small Lymphocyt... Chronic Lymphoc... Waldenstrom Mac... Mantle Cell Lym... Diffuse Large B... Richter's Trans... Follicular Lymp... Marginal Zone L...	Nemtabrutinib	18 Years -	ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Spots Global Cancer Trial Database for btk (brutons tyrosine kinase)