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RecruitingInterventionalPhase 3

A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib (MK-1026) Plus Venetoclax Versus Venetoclax Plus Rituximab in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least 1 Prior Therapy (BELLWAVE-010)

NCT ID: NCT05947851Sponsor: Merck Sharp & Dohme LLCLast updated: 2026-05-18

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).

Arms & interventions

  • DrugNemtabrutinib

    5, 20, 45, and 65 mg tablets

  • DrugVenetoclax

    10, 50, and 100 mg tablets

  • BiologicalRituximab

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

Outcome measures

Primary

  • 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: 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.

    Time frame: Up to approximately 71 months

Secondary

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

    Time frame: Up to approximately 46 months

  • Part 2: Overall Survival (OS)

    Time frame: Up to approximately 108 months

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

    Time frame: Up to approximately 71 months

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

    Time frame: Up to approximately 108 months

  • Part 2: Number of Participants Experiencing AEs

    Time frame: Up to approximately 28 months

  • Part 2: Number of Participants Discontinuing Study Treatment Due to AEs

    Time frame: Up to approximately 25 months

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No
Inclusion Criteria: * 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 Exclusion Criteria: * 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 * Participants who have not adequately recovered from major surgery or have ongoing surgical complications

Study locations (6)

Highlands Oncology Group ( Site 5405)

Springdale, Arkansas, 72762

Recruiting
Study Coordinator · Contact

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

Long Beach, California, 90806

Recruiting
Study Coordinator · Contact

Memorial Hospital West ( Site 5410)

Pembroke Pines, Florida, 33028

Recruiting
Study Coordinator · Contact

Oregon Health and Science University ( Site 5425)

Portland, Oregon, 97239-3011

Recruiting
Study Coordinator · Contact

Medical Oncology Associates, PS ( Site 5406)

Spokane, Washington, 99208

Recruiting
Study Coordinator · Contact

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

Madison, Wisconsin, 53792

Completed