Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)
PHASE2RECRUITING
The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), Richter's transformation, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia (WM).
Study details:
This study will be performed in 2 parts: Dose Escalation and Confirmation (Part 1) and Cohort Expansion (Part 2). Following determination of the recommended phase 2 dose (RP2D) in Part 1, the study plans to proceed with Part 2 using 8 disease-specific expansion cohorts (Cohorts A to H).
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before C1D1 (the first dose of study treatment)
- Has a life expectancy of at least 3 months, based on the investigator assessment
- Has the ability to swallow and retain oral medication
- Participants who are Hepatitis B surface antigen (HBsAg)-positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization
- Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
- Has adequate organ function
- Male participants agree to refrain from donating sperm and agree to either remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for at least the time required to eliminate the study intervention after last dose of study intervention
- Female participants assigned female sex at birth who are not pregnant or breastfeeding are eligible to participate if not a participant of childbearing potential (POCBP), or if a POCBP they either use a contraceptive method that is highly effective OR remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle during the intervention period and for at least to eliminate study intervention after the last dose of study intervention
- Participants with Human immunodeficiency virus (HIV) are eligible if they meet all of the following: the CD4 count is >350 cells/uL at screening, the HIV viral load is below the detectable level, are on a stable ART regimen for at least 4 weeks prior to study entry, and are compliant with their ART
- Has a confirmed diagnosis of Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) with at least 2 lines of prior therapy (Part 1 only)
- Part 2 Cohort A: CLL/SLL participants who are relapsed or refractory to prior therapy with a covalent, irreversible Bruton's tyrosine kinase inhibitor (BTKi), and a B-cell lymphoma 2 inhibitor (BCL2i). CLL participants must have received and failed, been intolerant to, or determined by their treating physician to be a poor phosphoinositide 3-kinase inhibitor (PI3Ki) candidate or ineligible for a PI3Ki per local guidelines
- Part 2 Cohort B: CLL/SLL participants who are relapsed or refractory following at least 1 line of prior therapy and are BTKi treatment naive
- Part 2 Cohort C: CLL/SLL participants with 17p deletion or tumor protein p53 (TP53) mutation who are relapsed or refractory following at least 1 line of prior therapy
- Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i.
- Has active disease for CLL/SLL clearly documented to initiate therapy
- For SLL participants in Part 2: Has evaluable core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate at Screening
- Has a confirmed diagnosis of and meets the following prior therapy requirements for Cohorts D to G
- Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D)
- Participants with pathologically confirmed Mantle-cell lymphoma (MCL), documented by either overexpression of cyclin D1 or t (11;14), who are relapsed or are refractory to chemoimmunotherapy and a covalent irreversible BTKi (Cohort E)
- Participants with Marginal zone lymphoma (MZL) who are relapsed or refractory to at least one prior line of systemic therapy including an anti-CD20-based regimen
- Participants with Follicular lymphoma (FL) who are relapsed or refractory to chemoimmunotherapy and immunomodulatory agents (such as lenalidomide based regimen) (Cohort G)
- Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral Computed tomography (CT) scan
- Has a lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate (Cohort D) at Screening
- Confirmed diagnosis of Waldenström's macroglobulinemia (WM); participants who are relapsed or refractory to standard therapies for WM including chemoimmunotherapy and a covalent irreversible BTKi
- Has active disease defined as 1 of the following: systemic symptoms, physical findings, laboratory abnormalities, coexisting disease
- Has measurable disease, satisfying any of the following: at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan (minimum measurement must be >15 mm in the longest diameter or >10 mm in the short axis); IgM ≥450 mg/dL; or bone marrow infiltration of 10%
- Has fresh bone marrow aspirate or a lymph node biopsy for biomarker analysis at Screening or a lymph node biopsy from an archival
Exclusion criteria
- Has active HBV/HCV infection (Part 1 and Part 2)
- Has a history of malignancy ≤3 years before providing documented informed consent. Participants with basal cell carcinoma of skin, squamous cell carcinoma of skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy are not excluded. Participants with low-risk, early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen <10 ng/mL) either treated with definitive intent or untreated in active surveillance with SD are not excluded
- Has active central nervous system (CNS) disease
- Has an active infection requiring systemic therapy
- Has received prior systemic anti-cancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before C1D1
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
- Has any clinically significant gastrointestinal abnormalities that might alter absorption
- History of severe bleeding disorders
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2
Study ID
NCT04728893
Intervention or treatment
DRUG: Nemtabrutinib
Conditions
- Hematologic Malignancies
- Waldenstroms Macroglobulinaemia
- Non-Hodgkins Lymphoma
- Chronic Lymphocytic Leukaemia
You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.
Research sites nearby
Closest Location:
Nepean Hospital-Nepean Cancer Care Centre ( Site 0204)
Select from list below to view details:
Nepean Hospital-Nepean Cancer Care Centre ( Site 0204)
Sydney, New South Wales, Australia
Box Hill Hospital ( Site 0203)
Box Hill, Victoria, Australia
Sir Charles Gairdner Hospital ( Site 0200)
Nedlands, Western Australia, Australia
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Who is running the clinical trial?
MS&DL
Merck Sharp & Dohme LLC
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Nemtabrutinib
| Drug: Nemtabrutinib |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) | DLTs will be defined as toxicities observed during the first 2 cycles (8 weeks) of Part 1 and include: Grade ≥3 nonhematologic toxicity (except Grade 3 nausea, vomiting, diarrhea, rash, fatigue, and uncontrolled hypertension which will not be considered a DLT unless lasting ≥72 hours despite optimal supportive care); Grade 4 hematologic toxicity lasting \>7 days (except Grade 3 lymphocytosis, Grade 4 platelet count decreased of any duration, or Grade 3 platelet count decreased if associated with bleeding); any Grade 3 or Grade 4 nonhematologic laboratory abnormality if values result in drug-induced liver injury, or medical intervention is required, or the abnormality leads to hospitalization, or the abnormality persists for \>1 week (with exceptions); missing \>25% of nemtabrutinib doses as a result of drug-related adverse events (AEs) during the first 2 cycles (8 weeks); Grade 5 toxicity. | Up to ~56 days (Cycles 1-2, cycle = 28 days) |
| Part 1: Number of participants experiencing adverse events (AEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 1. | Up to ~71 months |
| Part 1: Number of participants discontinuing study treatment due to AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to an AE will be reported for Part 1. | Up to ~42 months |
| Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR) | ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a complete response (CR), complete response with incomplete bone marrow 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 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. | Up to ~61 months |
| Part 2: ORR per Lugano criteria 2014 as assessed by ICR | 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): score of 1, 2 or 3 on the 5-point scale assessing fluorodeoxyglucose (FDG) metabolic activity in lymphomatous lesions (ranging from 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 the sum of the 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 or 5 on the FDG 5-point scale (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. | Up to ~61 months |
| Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR | 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 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). | Up to ~71 months |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Area Under the Curve (AUC) of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib AUC (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 1: Minimum Concentration (Cmin) of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib Cmin (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 1: Maximum Concentration (Cmax) of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib Cmax (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 1: ORR per iwCLL criteria 2018 as assessed by ICR | ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a CR, CRi, nPR, or 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 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. | Up to ~71 months |
| Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR | 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 PD 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. | Up to ~71 months |
| Part 2: Number of participants experiencing AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 2. | Up to ~61 months |
| Part 2: Number of participants discontinuing study treatment due to AEs | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to an AE will be reported for Part 2. | Up to ~42 months |
| Part 2: AUC of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib AUC (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 2: Cmin of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib Cmin (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 2: Cmax of Nemtabrutinib | Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib Cmax (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose \[up to \~57 days\]). Each cycle is 28 days. | At designated time points (up to ~57 days) |
| Part 2: DOR per iwCLL criteria 2018 as assessed by ICR | 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. | Up to ~61 months |
| Part 2: DOR per Lugano criteria 2014 as assessed by ICR | 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: score of 1, 2 or 3 on the 5-point scale assessing FDG metabolic activity in lymphomatous lesions (ranging from 1=no uptake above background to 5=uptake markedly higher than liver and/or new 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 score of 4 or 5 on the FDG 5-point scale (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. | Up to ~61 months |
| Part 2: DOR per IWWM criteria 2014 as assessed by ICR | 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). | Up to ~61 months |
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References
Clinical Trials Gov: Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)Other trials to consider
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