Recruiting
Phase 2
Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)
Condition(s) studied
Hematologic MalignanciesWaldenstroms MacroglobulinaemiaNon-Hodgkins LymphomaChronic Lymphocytic Leukaemia
Investigational drug(s) / intervention(s)
Nemtabrutinib
Nemtabrutinib: Nemtabrutinib tablets administered orally QD.
Study summary
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).
Eligibility
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
Part 1 and Part 2 (Cohorts A to C and J)
* 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. NOTE: As of Protocol Amendment 09, at least 10 CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi, BCL2i and noncovalent/reversible BTKi (all three classes of therapies are required) will be enrolled into Cohort J
* 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 (optional for participants enrolling in Part 1)
Part 2 (Cohorts D to G)
\- Has a confirmed diagnosis of and meets the following prior therapy requirements:
* 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) (including splenic, nodal, and extra nodal 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
Part 2 (Cohort H): 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
Primary outcome measure(s)
- Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) — Up to ~56 days (Cycles 1-2, cycle = 28 days)
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.
- Part 1: Number of participants experiencing adverse events (AEs) — Up to ~71 months
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.
- Part 1: Number of participants discontinuing study treatment due to AEs — Up to ~42 months
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.
- Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR) — Up to ~61 months
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.
- Part 2: ORR per Lugano criteria 2014 as assessed by ICR — Up to ~61 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): 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.
- Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR — Up to ~71 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 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).
Trial sites (121)
| Facility | City | Region | Status |
| Highlands Oncology Group ( Site 2728) |
Springdale |
Arkansas |
Recruiting |
| University of California San Diego Moores Cancer Center ( Site 2717) |
La Jolla |
California |
Recruiting |
| Lundquist Institute for Biomedical Innovation at Harbor-UCLA-Hematology and Medical Oncology ( Site 2724) |
Torrance |
California |
Completed |
| Colorado Blood Cancer Institute ( Site 2726) |
Denver |
Colorado |
Recruiting |
| The University of Louisville, James Graham Brown Cancer Center ( Site 2729) |
Louisville |
Kentucky |
Completed |
| Mayo Clinic - Rochester ( Site 2706) |
Rochester |
Minnesota |
Active Not Recruiting |
| Astera Cancer Care ( Site 2732) |
East Brunswick |
New Jersey |
Recruiting |
| John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704) |
Hackensack |
New Jersey |
Recruiting |
| Sanford Fargo Medical Center-Roger Maris Cancer Center ( Site 2708) |
Fargo |
North Dakota |
Completed |
| UT Southwestern-Harold C. Simmons Cancer Center ( Site 2730) |
Dallas |
Texas |
Recruiting |
| Medical Oncology Associates (Summit Cancer Centers) ( Site 2710) |
Spokane |
Washington |
Recruiting |
| Hospital Aleman ( Site 0102) |
Ciudad Autonoma de Buenos Aires |
Buenos Aires |
Recruiting |
| Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103) |
Buenos Aires |
Buenos Aires F.D. |
Recruiting |
| Fundacion Estudios Clinicos ( Site 0112) |
Rosario |
Santa Fe Province |
Recruiting |
| FUNDALEU ( Site 0104) |
Caba |
Argentina |
Recruiting |
| Hospital Privado Universitario de Córdoba ( Site 0107) |
Córdoba |
Argentina |
Recruiting |
| Fundacion Centro Oncologico de Integración Regional-Medical Oncology ( Site 0110) |
Mendoza |
Argentina |
Completed |
| Nepean Hospital-Nepean Cancer Care Centre ( Site 0204) |
Sydney |
New South Wales |
Completed |
| Box Hill Hospital ( Site 0203) |
Box Hill |
Victoria |
Recruiting |
| Sir Charles Gairdner Hospital ( Site 0200) |
Nedlands |
Western Australia |
Recruiting |
| Hospital das Clinicas FMUSP-Pesquisa Clínica Hematologia ( Site 0303) |
São Paulo |
São Paulo |
Recruiting |
| Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0300) |
Rio de Janeiro |
Brazil |
Recruiting |
| BP - A Beneficencia Portuguesa de São Paulo ( Site 0302) |
São Paulo |
Brazil |
Active Not Recruiting |
| Hospital Paulistano - Amil Clinical Research ( Site 0311) |
São Paulo |
Brazil |
Recruiting |
| Arthur J.E. Child Comprehensive Cancer Centre ( Site 0401) |
Calgary |
Alberta |
Recruiting |
| The Ottawa Hospital ( Site 0404) |
Ottawa |
Ontario |
Recruiting |
| Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406) |
Toronto |
Ontario |
Recruiting |
| CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0403) |
Montreal |
Quebec |
Recruiting |
| Jewish General Hospital ( Site 0400) |
Montreal |
Quebec |
Recruiting |
| Anhui Provincial Hospital ( Site 2808) |
Hefei |
Anhui |
Active Not Recruiting |
| Peking University Third Hospital-Hematology ( Site 2827) |
Beijing |
Beijing Municipality |
Recruiting |
| The Second Affiliated Hospital of Chongqing Medical University ( Site 2825) |
Chongqing |
Chongqing Municipality |
Active Not Recruiting |
| Sun Yat-sen University Cancer Center-Internal Medicine ( Site 2824) |
Guangzhou |
Guangdong |
Active Not Recruiting |
| Liuzhou People's Hospital ( Site 2817) |
Liuzhou |
Guangxi |
Recruiting |
| Guangxi Medical University Cancer Hospital ( Site 2814) |
Nanning |
Guangxi |
Recruiting |
| Henan Cancer Hospital-hematology department ( Site 2802) |
Zhengzhou |
Henan |
Recruiting |
| Wuhan Union Hospital ( Site 2816) |
Wuhan |
Hubei |
Recruiting |
| The Second Xiangya Hospital of Central South University ( Site 2820) |
Changsha |
Hunan |
Recruiting |
| Hunan Cancer Hospital ( Site 2822) |
Changsha |
Hunan |
Recruiting |
| Jiangsu Province Hospital ( Site 2823) |
Nanjing |
Jiangsu |
Recruiting |
+ 81 more sites — see the full list on the official registry below.