Hematological Malignancies
Conditions
Brief summary
The purpose of this study is to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of oral nemtabrutinib in Chinese participants at least 18 years of age who have Relapsed/Refractory hematologic malignancies.
Interventions
DRUGNemtabrutinib
Nemtabrutinib tablets will be administered orally QD.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Relapsed or refractory participants with a diagnosis of B-cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) or Waldenström's Macroglobulinemia (WM) who have received no more than 4 prior standard systemic therapies. Participants must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens and those with low grade lymphoma must be progressing and requiring treatment * Must have received prior systemic treatment before joining this study * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 * HBV/HCV viral load undetectable or no history of HBV/HCV * Has adequate organ function * Male participants agree to be abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 30 days after the last dose of the study intervention * Female participant is not a Women of Child Bearing Potential (WOCBP) or is a WOCBP using contraception during the intervention period and for at least 30 days after the last dose of the study intervention
Exclusion criteria
* Has a history of prior cancer within \<3 years, except for adequately treated basal cell or squamous cell carcinoma of the skin, cervical cancer in situ, or other in situ carcinomas * Has active primary tumor involvement of central nervous system (CNS) disease * Has an active infection requiring systemic therapy * Has a known history of Human Immunodeficiency Virus (HIV) infection * Has an uncontrolled illness including but not limited to ongoing symptomatic congestive heart failure (New York Heart Association Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, and psychiatric illness * Had immunotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product ≤4 weeks prior to treatment initiation * Has any clinically significant gastrointestinal abnormalities that might alter absorption
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants who Experience Adverse Events (AEs) | Up to ~ 35 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. |
| Number of Participants Discontinuing Study Treatment due to AEs | Up to ~ 35 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. |
| Maximum Concentration (Cmax) of Nemtabrutinib | Day 1 of Cycles 1 and 2: Pre-dose,1, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2 hours post-dose (up to ~57 days). Each cycle is 28 days | Cmax is the maximum concentration of nemtabrutinib observed in plasma. Blood samples collected at designated timepoints will be used to determine Cmax. |
| Minimum Concentration (Cmin) of Nemtabrutinib | Day 1 of Cycles 1 and 2: Pre-dose,1, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2 hours post-dose (up to ~57 days). Each cycle is 28 days | Cmin is the minimum concentration of nemtabrutinib observed in plasma. Blood samples collected at designated timepoints will be used to determine Cmin. |
| Area Under the Plasma Concentration-Time Curve from 0 to 24 Hours (AUC0-24) of Nemtabrutinib | Day 1 of Cycles 1 and 2: Pre-dose,1, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2 hours post-dose (up to ~57 days). Each cycle is 28 days | AUC0-24 is the area under the curve of plasma concentration of nemtabrutinib from time 0 to 24 hours. Blood samples collected at designated timepoints will be used to determine AUC0-24. |
| Time to Maximum Concentration (Tmax) of Nemtabrutinib | Day 1 of Cycles 1 and 2: Pre-dose,1, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2 hours post-dose (up to ~57 days). Each cycle is 28 days | Tmax is the time to reach maximum concentration of nemtabrutinib. Blood samples collected at designated timepoints will be used to determine Tmax. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 as Assessed by the Investigator | Up to ~ 35 months | ORR per iwCLL criteria 2018 is defined as the percentage of participants achieving a complete response (CR), complete response with incomplete bone marrow (BM) recovery (CRi), nodular partial response (nPR) or partial response (PR). 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). CRi is defined as meeting CR criteria but with incomplete bone marrow recovery. nPR is defined as having features of CR but with lymphoid nodules in the marrow. 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 per International Workshop on Waldenström's Macroglobulinemia (IWWM) Criteria 2014 as Assessed by the Investigator | Up to ~ 35 months | ORR per IWWM criteria 2014 is defined as the percentage of participants achieving a CR, very good partial response (VGPR), or PR. CR is defined as all lymph nodes are normal in size (none ≥15 mm), liver and spleen normal in size, serum immunoglobulin M (IgM) values in the normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with a second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR is defined as ≥50% decrease from baseline in sum of product of diameter (SPD) of lymph nodes (if abnormal at baseline) ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal) and ≥90% decrease from baseline in serum IgM or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline) ≥50% decrease from baseline in serum IgM and ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal). |
| ORR per Lugano Criteria 2014 as Assessed by the Investigator | Up to ~ 35 months | ORR per Lugano criteria 2014 is defined as the percentage of participants achieving a CR or PR. CR defined as EITHER CR by imaging (computed tomography \[CT\]): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR complete metabolic response (CMR): assessing fluorodeoxyglucose (FDG) metabolic activity in lymphomatous lesions AND bone marrow normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the SPD of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR Partial Metabolic Response (PMR) with no new lesions and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities. |
| Duration of Response (DOR) per iwCLL Criteria 2018 as Assessed by the Investigator | Up to ~ 35 months | For participants with CR, CRi, nPR, or PR per iwCLL 2018 criteria, DOR is defined as the time from the first documented evidence of objective response until disease progression 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). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. 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 per IWWM Criteria 2014 as Assessed by the Investigator | Up to ~ 35 months | For participants with CR, VGPR, or PR per IWWM criteria 2014, DOR defined as the time from first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as all lymph nodes normal in size (none ≥15 mm), liver and spleen normal in size, serum IgM values in normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal), and ≥90% decrease from baseline in serum IgM, or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in serum IgM, and ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal). |
| DOR per Lugano Criteria 2014 as Assessed by the Investigator | Up to ~ 35 months | For participants with CR or PR per Lugano criteria 2014, DOR is defined as the time from the first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as EITHER CR by imaging (CT): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR CMR: assessing FDG metabolic activity in lymphomatous lesions AND BM normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the SPD of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR PMR with no new lesions and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities. |
Countries
China
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Outcome results
None listed