A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010).

NCT05947851 | Recruiting Phase 3 DMC FDA Drug

• 5 other identifiers: 1026-010MK-1026-010BELLWAVE-0102022-501560-17-00U1111-1281-1520
• Study Type: interventional
• Target: 735
• Locations: 18 countries
• Sites: 52

Brief Summary

The purpose of this study is to assess the safety and tolerability and to confirm the dose of nemtabrutinib in combination with venetoclax in participants with R/R CLL/SLL. The primary study hypotheses are that the combination of nemtabrutinib plus venetoclax is superior to VR with respect to progression-free survival (PFS) per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria as assessed by blinded independent central review (BICR).

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Chronic Lymphocytic; Small-Cell Lymphoma; Lymphoma, Small Lymphocytic; CLL; SLL

Outcome Measures

Primary Outcomes (4)

• Part 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)

  DLT evaluation period is defined as 8 weeks after the first dose of the combination treatment of nemtabrutinib plus venetoclax Cycle 2 Day 1 in Part 1 + 4 weeks follow up. Each cycle is 4 weeks. DLTs are: 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 or venetoclax doses as a result of drug-related adverse events during the first 2 cycles; Grade 5 toxicity.

  Up to approximately 12 Weeks

• 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 approximately 28 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 AEs will be reported for Part 1.

  Up to approximately 25 months

• Part 2: PFS per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Blinded Independent Central Review (BICR)

  PFS is defined as the time from randomization to the first documented disease progression per iwCLL criteria 2018 as accessed by BICR, or death due to any cause, whichever occurs first. PFS will be presented.

  Up to approximately 71 months

Secondary Outcomes (6)

• Part 2: Undetectable Minimal Residual Disease (MRD) Rate in Bone Marrow as Assessed by Central Laboratory

  Up to approximately 46 months

• Part 2: Overall Survival (OS)

  Up to approximately 108 months

• Part 2: Objective Response Rate (ORR) per iwCLL Criteria 2018 as Assessed by BICR

  Up to approximately 71 months

• Part 2: Duration of Response (DOR) per iwCLL Criteria 2018 as Assessed by BICR

  Up to approximately 108 months

• Part 2: Number of Participants Experiencing AEs

  Up to approximately 28 months

Study Arms (2)

Nemtabrutinib + Venetoclax

EXPERIMENTAL

Participants will receive nemtrabrutinib oral tablets at specified doses daily starting at Cycle 1 Day 1 (C1D1) and venetoclax oral tablets at doses of 20 mg up to 400 mg daily starting at Cycle 2 Day 1 (C2D1) up to 2 years post C2D1 or until progressive disease (PD) or discontinuation. A cycle = 4 weeks.

Drug: Nemtabrutinib; Drug: Venetoclax

Venetoclax + Rituximab

ACTIVE COMPARATOR

Participants will receive venetoclax oral tablets at doses from 20 mg up to 400 mg daily starting at C1D1 on 4-week cycles up to 2 years and rituximab or biosimilar at 375 mg/m\^2 up to 500 mg/m2 intravenous infusion once per 28-day cycle starting at C2D1, for 6 total cycles. Treatment will continue until progressive disease (PD) or discontinuation.

Drug: Venetoclax; Biological: Rituximab

Interventions

Nemtabrutinib DRUG

5, 20, 45, and 65 mg tablets

Also known as: ARQ 531, MK-1026

Nemtabrutinib + Venetoclax

Venetoclax DRUG

10, 50, and 100 mg tablets

Also known as: ABT-199, GDC-0199

Nemtabrutinib + Venetoclax; Venetoclax + Rituximab

Rituximab BIOLOGICAL

100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Venetoclax + Rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and active disease clearly documented to initiate therapy
• Deletion (Del) (17p) status, tumor protein 53 (TP53) mutation status, and immunoglobulin heavy chain gene (IGHV) mutation status results required before randomization for Part 2 participants only
• Relapsed or refractory to at least 1 prior available therapy
• Have at least 1 marker of disease burden
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization
• Has a life expectancy of at least 3 months
• 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 deoxyribonucleic acid (DNA) viral load before randomization
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening
• Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria
• Participants with adequate organ function with specimens collected within 7 days before the start of study intervention
• If capable of producing sperm, participant agrees to eliminate Nemtabrutinib: 12 days, Venetoclax: 1 month (30 days), Rituximab (rituximab biosimilar): not applicable; abstains from penile-vaginal intercourse as their preferred and usual lifestyle; OR uses prescribed contraception
• Participant assigned female sex at birth are eligible to participate if not pregnant or breastfeeding and are not a person of childbearing potential (POCBP) OR is a POCBP and uses a contraceptive method that is highly effective, has a negative highly sensitive pregnancy test, and abstains from breastfeeding

You may not qualify if:

• Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection
• Has gastrointestinal (GI) dysfunction that may affect drug absorption
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
• Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL
• Has an active infection requiring systemic therapy, such as intravenous (IV) antibiotics, during screening
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease and/or acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening
• Clinically significant cardiovascular disease
• Has a known allergy/sensitivity to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar), or any of the excipients
• Has history of severe bleeding disorders (eg, hemophilia)
• Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization
• Has received prior B-cell lymphoma 2 inhibitor(s) (BCL2i) within ≤ 12 months before randomization or has received prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids
• Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors.
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention
• Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration
• Has a known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (52)

Highlands Oncology Group ( Site 5405)

Springdale, Arkansas, 72762, United States

RECRUITING

MemorialCare Health System - Long Beach Medical Center ( Site 5421)

Long Beach, California, 90806, United States

RECRUITING

Memorial Hospital West ( Site 5410)

Pembroke Pines, Florida, 33028, United States

RECRUITING

Oregon Health and Science University ( Site 5425)

Portland, Oregon, 97239-3011, United States

RECRUITING

Medical Oncology Associates, PS ( Site 5406)

Spokane, Washington, 99208, United States

RECRUITING

University of Wisconsin Hospital and Clinics-Carbone Cancer Center ( Site 5423)

Madison, Wisconsin, 53792, United States

ACTIVE NOT RECRUITING

Instituto Alexander Fleming ( Site 1005)

Ciudad Autónoma de Buenos Aires, Buenos Aires, C1426ANZ, Argentina

RECRUITING

Instituto de Investigaciones Clínicas Mar del Plata ( Site 1007)

Mar del Plata, Buenos Aires, B7600FZO, Argentina

RECRUITING

Sanatorio Parque ( Site 1003)

Rosario, Santa Fe Province, S2000DSV, Argentina

RECRUITING

Centro Medico Fleischer ( Site 1006)

Buenos Aires, 1414, Argentina

RECRUITING

Hospital Aleman-oncohematologic diseases ( Site 1001)

Buenos Aires, C1118AAT, Argentina

RECRUITING

Royal Adelaide Hospital ( Site 1104)

Adelaide, South Australia, 5000, Australia

RECRUITING

Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103)

Melbourne, Victoria, 3021, Australia

RECRUITING

UZ Leuven-Hematology ( Site 1200)

Leuven, Vlaams-Brabant, 3000, Belgium

RECRUITING

ZAS Cadix ( Site 1203)

Antwerp, 2030, Belgium

RECRUITING

ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308)

São Paulo, 01246-000, Brazil

ACTIVE NOT RECRUITING

The Moncton Hospital ( Site 1414)

Moncton, New Brunswick, E1C 6Z8, Canada

RECRUITING

IC La Serena Research ( Site 1506)

La Serena, Coquimbo Region, 1720430, Chile

RECRUITING

Centro de Estudios Clínicos SAGA-CECSAGA ( Site 1509)

Santiago, Region M. de Santiago, 7500653, Chile

RECRUITING

FALP-UIDO ( Site 1500)

Santiago, Region M. de Santiago, 7500921, Chile

RECRUITING

Clínica Inmunocel ( Site 1511)

Santiago, Region M. de Santiago, 7580206, Chile

RECRUITING

Biocenter ( Site 1507)

Concepción, Región del Biobío, 4070196, Chile

RECRUITING

Fundación Valle del Lili ( Site 1703)

Cali, Valle del Cauca Department, 760032, Colombia

RECRUITING

Hopital Claude Huriez - CHU de Lille ( Site 2107)

Lille, Nord, 59037, France

RECRUITING

Centre Hospitalier Universitaire Estaing ( Site 2105)

Clermont-Ferrand, Puy-de-Dome, 63100, France

RECRUITING

CHD Vendee ( Site 2100)

La Roche-sur-Yon, Vendee, 85925, France

RECRUITING

Klinikum Mutterhaus der Borromäerinnen-Innere Medizin I ( Site 2203)

Trier, Rhineland-Palatinate, 54290, Germany

RECRUITING

Universitätsklinikum Leipzig-Medical Department I - Hematology and Celltherapy ( Site 2201)

Leipzig, Saxony, 04103, Germany

RECRUITING

Rambam Health Care Campus ( Site 2801)

Haifa, 3109601, Israel

RECRUITING

Hadassah Medical Center-Hemato-Oncology ( Site 2812)

Jerusalem, 9112001, Israel

RECRUITING

Sheba Medical Center-Hemato Oncology ( Site 2809)

Ramat Gan, 5265601, Israel

RECRUITING

Sourasky Medical Center ( Site 2811)

Tel Aviv, 6423906, Israel

RECRUITING

Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e Cesare Arrigo ( Site 2906)

Alessandria, 15121, Italy

RECRUITING

Ospedale San Raffaele-Programma di Ricerca Strategica sulla LLC ( Site 2902)

Milan, 20132, Italy

RECRUITING

Arcispedale Santa Maria Nuova-Hematology ( Site 2900)

Reggio Emilia, 42123, Italy

RECRUITING

Centro de Infusion Superare ( Site 3314)

Mexico City, Mexico City, 03100, Mexico

RECRUITING

Health Pharma Professional Research S.A. de C.V: ( Site 3301)

Mexico City, Mexico City, 03100, Mexico

RECRUITING

Centro de Investigacion Clinica Chapultepec ( Site 3309)

Morelia, Michoacán, 58260, Mexico

RECRUITING

Auxilio Mutuo Cancer Center ( Site 3900)

San Juan, 00918, Puerto Rico

RECRUITING

Alberts Cellular Therapy. ( Site 4401)

Pretoria, Gauteng, 0181, South Africa

RECRUITING

Groote Schuur Hospital ( Site 4400)

Cape Town, Western Cape, 7925, South Africa

RECRUITING

Haemalife ( Site 4407)

Kuilsriver, Western Cape, 7580, South Africa

RECRUITING

Instituto Catalan de Oncologia - Hospital Duran i Reynals-Haematology Department ( Site 4601)

L'Hospitalet Del Llobregat, Barcelona, 08908, Spain

RECRUITING

HOSPITAL UNIVERSITARIO QUIRONSALUD MADRID ( Site 4602)

Pozuelo de Alarcón, Madrid, 28223, Spain

RECRUITING

HOSPITAL CLINICO DE VALENCIA-HEMATOLOGY ( Site 4603)

Valencia, Valenciana, Comunitat, 46010, Spain

RECRUITING

Ege Universitesi Hastanesi ( Site 4902)

Bornova, İzmir, 35100, Turkey (Türkiye)

RECRUITING

Namik Kemal University Medical Faculty-Hematology ( Site 4912)

Tekirdağ, Tekirdas, 59100, Turkey (Türkiye)

RECRUITING

Ankara Universitesi Tip Fakultesi Hastanesi-hematology ( Site 4913)

Ankara, 06100, Turkey (Türkiye)

RECRUITING

Mega Medipol-Hematology ( Site 4904)

Istanbul, 34214, Turkey (Türkiye)

RECRUITING

TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi ( Site 4906)

Istanbul, 34722, Turkey (Türkiye)

RECRUITING

City Hospital, Nottingham University Hospitals-Hematology ( Site 5002)

Nottingham, England, NG5 1PF, United Kingdom

RECRUITING

University College London Hospital-Cancer Clinical Trials Unit ( Site 5001)

London-Camden, London, City of, NW1 2PG, United Kingdom

RECRUITING

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

ARQ531; venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Central Study Contacts

Toll Free Number

CONTACT

1-888-577-8839; Trialsites@msd.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: In Part 1, Dose Confirmation will be determined by modified toxicity probability interval (mTPI) design, where participants will be assigned to two treatment groups, Nemtabrutinib + Venetoclax in parallel with Nemtabrutinib + Venetoclax. Part 2 will be an Efficacy Expansion where all participants will be randomized 1:1 to Nemtabrutinib Part 1 Dose Selection plus Venetoclax or Venetoclax plus Rituximab (VR) (or Rituximab biosimilar) for the duration of the study.

Study Record Dates

• First Submitted: July 7, 2023
• First Posted: July 17, 2023
• Study Start: August 8, 2023
• Primary Completion (Estimated): June 1, 2032
• Study Completion (Estimated): July 1, 2035
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

BE (2); ZA (3); CO (1); IT (3); ES (3); CA (1); IL (4); AR (5); BR (1); TU (5); GB (2); CL (5); PR (1); AU (2); ME (3); US (6); DE (2); FR (3)