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
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
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.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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