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NCT04728893PHASE2Recruiting

Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)

Merck Sharp & Dohme LLC

Start Date

4/5/2021

Completion Date

1/4/2029

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).

Detailed Description

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

Age Range: 18 years to No maximum

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

Interventions

DRUG

Nemtabrutinib

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Conditions

Hematologic MalignanciesWaldenstroms MacroglobulinaemiaNon-Hodgkins LymphomaChronic Lymphocytic Leukaemia

Locations

Highlands Oncology Group ( Site 2728)

Springdale, Arkansas 72762

United States

University of California San Diego Moores Cancer Center ( Site 2717)

La Jolla, California 92093-0698

United States

Lundquist Institute for Biomedical Innovation at Harbor-UCLA-Hematology and Medical Oncology ( Site 2724)

Torrance, California 90502

United States

Colorado Blood Cancer Institute ( Site 2726)

Denver, Colorado 80218

United States

The University of Louisville, James Graham Brown Cancer Center ( Site 2729)

Louisville, Kentucky 40202

United States

Mayo Clinic - Rochester ( Site 2706)

Rochester, Minnesota 55905

United States

Astera Cancer Care ( Site 2732)

East Brunswick, New Jersey 08816

United States

John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704)

Hackensack, New Jersey 07601

United States

Sanford Fargo Medical Center-Roger Maris Cancer Center ( Site 2708)

Fargo, North Dakota 58102

United States

UT Southwestern-Harold C. Simmons Cancer Center ( Site 2730)

Dallas, Texas 75390

United States

Medical Oncology Associates (Summit Cancer Centers) ( Site 2710)

Spokane, Washington 99208

United States

Hospital Aleman ( Site 0102)

Ciudad Autonoma de Buenos Aires, Buenos Aires C1118AAT

Argentina

Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103)

Buenos Aires, Buenos Aires F.D. C1431FWO

Argentina

Fundacion Estudios Clinicos ( Site 0112)

Rosario, Santa Fe Province S2000DEJ

Argentina

FUNDALEU ( Site 0104)

Caba, C1114AAN

Argentina

Hospital Privado Universitario de Córdoba ( Site 0107)

Córdoba, X5016KEH

Argentina

Fundacion Centro Oncologico de Integración Regional-Medical Oncology ( Site 0110)

Mendoza, M5500AYB

Argentina

Nepean Hospital-Nepean Cancer Care Centre ( Site 0204)

Sydney, New South Wales 2747

Australia

Box Hill Hospital ( Site 0203)

Box Hill, Victoria 3128

Australia

Sir Charles Gairdner Hospital ( Site 0200)

Nedlands, Western Australia 6009

Australia

Hospital das Clinicas FMUSP-Pesquisa Clínica Hematologia ( Site 0303)

São Paulo, São Paulo 05403-000

Brazil

Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0300)

Rio de Janeiro, 20231-050

Brazil

BP - A Beneficencia Portuguesa de São Paulo ( Site 0302)

São Paulo, 01321-001

Brazil

Hospital Paulistano - Amil Clinical Research ( Site 0311)

São Paulo, 01321-001

Brazil

Arthur J.E. Child Comprehensive Cancer Centre ( Site 0401)

Calgary, Alberta T2N 5G2

Canada

The Ottawa Hospital ( Site 0404)

Ottawa, Ontario K1H 8L6

Canada

Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406)

Toronto, Ontario M5G 2M9

Canada

CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0403)

Montreal, Quebec H1T 2M4

Canada

Anhui Provincial Hospital ( Site 2808)

Hefei, Anhui 230071

China

Peking University Third Hospital-Hematology ( Site 2827)

Beijing, Beijing Municipality 100191

China

The Second Affiliated Hospital of Chongqing Medical University ( Site 2825)

Chongqing, Chongqing Municipality 400072

China

Sun Yat-sen University Cancer Center-Internal Medicine ( Site 2824)

Guangzhou, Guangdong 510060

China

Liuzhou People's Hospital ( Site 2817)

Liuzhou, Guangxi 545006

China

Guangxi Medical University Cancer Hospital ( Site 2814)

Nanning, Guangxi 530028

China

Henan Cancer Hospital-hematology department ( Site 2802)

Zhengzhou, Henan 450008

China

Wuhan Union Hospital ( Site 2816)

Wuhan, Hubei 430022

China

The Second Xiangya Hospital of Central South University ( Site 2820)

Changsha, Hunan 410011

China

Hunan Cancer Hospital ( Site 2822)

Changsha, Hunan 410013

China

Jiangsu Province Hospital ( Site 2823)

Nanjing, Jiangsu 210029

China

The Affiliated Hospital of Xuzhou Medical College ( Site 2818)

Xuzhou, Jiangsu 221000

China

The First Affiliated Hospital of Nanchang University ( Site 2815)

Nanchang, Jiangxi 330006

China

The First Hospital of Jilin University-Hematology ( Site 2803)

Changchun, Jilin 130021

China

Fudan University Shanghai Cancer Center ( Site 2801)

Shanghai, Shanghai Municipality 200032

China

Huashan Hospital, Fudan University ( Site 2821)

Shanghai, Shanghai Municipality 200040

China

West China Hospital Sichuan University ( Site 2810)

Chengdu, Sichuan 610041

China

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Unio ( Site 2800)

Tianjin, Tianjin Municipality 301617

China

The First Affiliated Hospital, Zhejiang University ( Site 2826)

Hangzhou, Zhejiang 310002

China

Fakultní nemocnice Brno Bohunice-Interni hematologicka a onkologicka klinika ( Site 0600)

Brno, Brno-mesto 625 00

Czechia

Fakultni nemocnice Hradec Kralove ( Site 0601)

Hradec Králové, 500 05

Czechia

Aarhus University Hospital ( Site 0702)

Aarhus N, Central Jutland 8200

Denmark

Aalborg Universitetshospital ( Site 0703)

Aalborg, North Denmark 9000

Denmark

Sjaellands Universitetshospital Roskilde ( Site 0701)

Roskilde, Region Sjælland 4000

Denmark

Odense University Hospital ( Site 0705)

Odense C, Region Syddanmark 5000

Denmark

Centre Hospitalier Universitaire de Nice - Hôpital l'Archet ( Site 0810)

Nice, Alpes-Maritimes 06202

France

Centre Hospitalier Lyon-Sud ( Site 0804)

Pierre-Bénite, Auvergne-Rhône-Alpes 69495

France

Institut Paoli-Calmettes ( Site 0803)

Marseille, Bouches-du-Rhone 13009

France

Centre Hospitalier de Versailles ( Site 0809)

Le Chesnay, Yvelines 78150

France

Hopital Saint Louis ( Site 0805)

Paris, 75010

France

Universitaetsklinikum Ulm. ( Site 0906)

Ulm, Baden-Wurttemberg 89081

Germany

Universitaetsklinikum Koeln ( Site 0901)

Cologne, North Rhine-Westphalia 50937

Germany

St. Marien-Krankenhaus Siegen ( Site 0914)

Siegen, North Rhine-Westphalia 57072

Germany

Universitaetsklinikum Carl Gustav Carus ( Site 0902)

Dresden, Saxony 01307

Germany

Pecsi Tudomanyegyetem Altalanos Orvostudomanyi Kar ( Site 1202)

Pécs, Baranya 7624

Hungary

Debreceni Egyetem Klinikai Kozpont ( Site 1201)

Debrecen, Hajdú-Bihar 4032

Hungary

Szabolcs Szatmár Bereg Vármegyei Oktatókórház ( Site 1206)

Nyíregyháza, Szabolcs-Szatmár-Bereg 4400

Hungary

Orszagos Onkologiai Intezet ( Site 1200)

Budapest, 1122

Hungary

Beaumont Hospital ( Site 2900)

Dublin, Dublin 9

Ireland

University Hospital Limerick ( Site 2903)

Limerick, V94 F858

Ireland

Ha Emek Medical Center ( Site 1305)

Afula, 1834111

Israel

Soroka Medical Center ( Site 1307)

Beersheba, 8457108

Israel

Rambam Medical Center ( Site 1301)

Haifa, 3109601

Israel

Hadassah Ein Karem Jerusalem ( Site 1300)

Jerusalem, 9112001

Israel

Chaim Sheba Medical Center ( Site 1302)

Ramat Gan, 5262001

Israel

Kaplan Medical Center ( Site 1304)

Rehovot, 76100

Israel

Sourasky Medical Center ( Site 1303)

Tel Aviv, 6423906

Israel

Istituto Tumori Giovanni Paolo II ( Site 1409)

Bari, 70124

Italy

A.O. Universitaria Policlinico S. Orsola-Malpighi ( Site 1400)

Bologna, 40138

Italy

ASST Spedali Civili di Brescia ( Site 1408)

Brescia, 25123

Italy

IRCCS Ospedale San Raffaele ( Site 1402)

Milan, 20132

Italy

Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1403)

Naples, 80131

Italy

Fondazione IRCCS Policlinico San Matteo ( Site 1407)

Pavia, 27100

Italy

IRCCS - Arcispedale Santa Maria Nuova ( Site 1405)

Reggio Emilia, 42123

Italy

Policlinico Umberto I ( Site 1404)

Roma, 00161

Italy

Pratia MCM Krakow ( Site 1601)

Krakow, Lesser Poland Voivodeship 30-727

Poland

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu ( Site 1606)

Wroclaw, Lower Silesian Voivodeship 50-367

Poland

Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Kilinka Onkologii I Hematologii ( Site 1608)

Warsaw, Masovian Voivodeship 02-781

Poland

Szpital Wojewódzki w Opolu-Hematology Department ( Site 1607)

Opole, Opole Voivodeship 45-061

Poland

Szpitale Pomorskie Sp. z o.o. ( Site 1600)

Gdynia, Pomeranian Voivodeship 81-519

Poland

Spitalul Clinic Colțea ( Site 1805)

Bucharest, Bucharest 030171

Romania

Ovidius Clinical Hospital ( Site 1804)

Ovidiu, Constanța County 905900

Romania

Centrul de Diagnostic si Tratament Oncologic Brasov ( Site 1802)

Brasov, 500052

Romania

Institutul Regional de Oncologie Iasi ( Site 1801)

Iași, 700483

Romania

Severance Hospital Yonsei University Health System ( Site 2201)

Seoul, 03722

South Korea

Samsung Medical Center ( Site 2200)

Seoul, 06351

South Korea

Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 2000)

L'Hospitalet de Llobregat, Barcelona 08908

Spain

Hospital Universitario de Salamanca ( Site 2002)

Salamanca, Castille and León 37007

Spain

CHUAC-Complejo Hospitalario Universitario A Coruña ( Site 2005)

A Coruña, La Coruna 15006

Spain

Hospital General Universitario de Alicante ( Site 2007)

Alicante, 03010

Spain

Hospital Universitari Vall d'Hebron ( Site 2001)

Barcelona, 08035

Spain

Hospital Universitario 12 de Octubre ( Site 2003)

Madrid, 28041

Spain

Hospital Puerta de Hierro ( Site 2009)

Madrid, 28222

Spain

Inselspital Bern ( Site 2303)

Bern, Canton of Bern 3010

Switzerland

Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 2302)

Bellinzona, Canton Ticino 6500

Switzerland

Mega Medipol-Hematology ( Site 2406)

Stanbul, Istanbul 34214

Turkey (Türkiye)

Ankara Universitesi Tip Fakultesi Cebeci Hastanesi ( Site 2400)

Ankara, 06590

Turkey (Türkiye)

VKV Amerikan Hastanesi ( Site 2403)

Istanbul, 34365

Turkey (Türkiye)

Sisli Florence Nightingale Hastanesi ( Site 2407)

Istanbul, 34381

Turkey (Türkiye)

Dokuz Eylül Üniversitesi-Hematology ( Site 2402)

Izmir, 35340

Turkey (Türkiye)

MNPE ClinCenter of Oncology,Hematology,Transplantology and Palliative Care of CherkasyRegCouncil ( Site 2509)

Cherkassy, Cherkasy Oblast 18009

Ukraine

Communal non-profit enterprise "Regional clinical hospital o-Hematology Department ( Site 2510)

Ivano-Frankivsk, Ivano-Frankivsk Oblast 76008

Ukraine

Instit. of Blood Transfusion Medicine of the National Academy ( Site 2506)

Lviv, Lviv Oblast 79044

Ukraine

National Cancer Institute ( Site 2507)

Kyiv, 03022

Ukraine

Bristol Haematology and Oncology Centre ( Site 2610)

Bristol, Bristol, City of BS2 8ED

United Kingdom

Nottingham University Hospitals NHS Trust. City Hospital Campus ( Site 2601)

Nottingham, England NG5 1PF

United Kingdom

GenesisCare - Windsor ( Site 2608)

Windsor, England SL4 3HD

United Kingdom

Sarah Cannon Research Institute UK ( Site 2612)

London, London, City of W1G 6AD

United Kingdom

GenesisCare - Oxford ( Site 2607)

Oxford, Oxfordshire OX4 6LB

United Kingdom

GenesisCare - Cambridge ( Site 2611)

Newmarket, Suffolk CB8 7XN

United Kingdom

The Royal Marsden NHS Foundation Trust. ( Site 2606)

Sutton, Surrey SM2 5PT

United Kingdom

The Christie NHS Foundation Trust ( Site 2602)

Manchester, M20 4BX

United Kingdom