Chronic Lymphocytic Leukemia, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Lymphoma, B-Cell, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Richter's Transformation, Small Lymphocytic Lymphoma, Waldenstrom Macroglobulinemia
Conditions
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
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.
Interventions
DRUGNemtabrutinib
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.
Sponsors
ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single group assignment (definition : A type of intervention model describing a clinical trial in which all participants receive the same intervention/treatment.)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants Experiencing Dose Limiting Toxicity (DLT) | Cycle 1 (up to 28 days) | 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) | Up to approximately 86 months | 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 | Up to approximately 86 months | 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. |
| 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 | Up to approximately 64 months | 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 | Up to approximately 64 months | 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
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Number of Participants Who Experienced an AE | Up to approximately 64 months | 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 2: Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 64 months | 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. |
| 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) | Blood samples will be collected at prespecified time points to determine Tmax of nemtabrutinib. |
| 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) | 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 | Cycles 1-92: Days 1, 2: Predose and up to 24 hours postdose (each cycle length = 28 days, up to approximately 86 months) | Blood samples will be collected at prespecified time points to determine AUC 0-24hrs of nemtabrutinib. |
| Terminal Elimination Half-Life (t1/2) 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) | 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 | Up to approximately 64 months | 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 D-H: ORR per Lugano classification as Assessed by the Investigator | Up to approximately 64 months | 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. |
| Phase 2: Expansion Cohorts A, B, H: Duration of Response (DOR) per iwCLL Criteria as Assessed by the Investigator | Up to approximately 64 months | 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 | Up to approximately 64 months | 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. |
Countries
United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed