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)

Leukemia, Lymphocytic, Chronic, B-Cell Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05947851
• Other study ID #: 1026-010
• Secondary ID: MK-1026-010BELLW
• Status: Recruiting
• Phase: Phase 3
• Start date: August 8, 2023
• Est. completion date: June 27, 2033

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 720
• Est. completion date: June 27, 2033
• Est. primary completion date: June 27, 2033
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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, immunoglobulin heavy chain gene (IGHV) mutation status and Bruton's tyrosine kinase (BTK)-C481 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 3 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.
• Has QT interval corrected (QTc) prolongation or other significant electrocardiogram (ECG) abnormalities.
• 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) including venetoclax or Non-covalent Bruton's tyrosine kinase inhibitor (BTKi).
• 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.

Related Conditions & MeSH terms

• CLL
• Leukemia
• Leukemia, Chronic Lymphocytic
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Small Lymphocytic
• SLL
• Small-Cell Lymphoma

Intervention

Drug:
• Nemtabrutinib
5 and 20 mg tablets
• Venetoclax
10, 50, and 100 mg tablets

Biological:
• Rituximab
100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Locations

Country	Name	City	State
Argentina	Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Hematology ( Site 1002)	Buenos Aires	Caba
Argentina	Centro Medico Fleischer ( Site 1006)	Buenos Aires
Argentina	Hospital Aleman-oncohematologic diseases ( Site 1001)	Buenos Aires	Caba
Argentina	Instituto Alexander Fleming ( Site 1005)	Ciudad Autónoma de Buenos Aires	Buenos Aires
Argentina	Instituto de Investigaciones Clínicas Mar del Plata ( Site 1007)	Mar del Plata	Buenos Aires
Argentina	Sanatorio Parque ( Site 1003)	Rosario	Santa Fe
Australia	Royal Adelaide Hospital ( Site 1104)	Adelaide	South Australia
Australia	Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103)	Melbourne	Victoria
Brazil	ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308)	São Paulo	Sao Paulo
Canada	The Moncton Hospital ( Site 1414)	Moncton	New Brunswick
Canada	Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Univer	Sherbrooke	Quebec
Chile	Biocenter ( Site 1507)	Concepción	Biobio
Chile	IC La Serena Research ( Site 1506)	La Serena	Coquimbo
Chile	Centro de Estudios Clínicos SAGA-CECSAGA ( Site 1509)	Santiago	Region M. De Santiago
Chile	Clínica Inmunocel ( Site 1511)	Santiago	Region M. De Santiago
Chile	FALP-UIDO ( Site 1500)	Santiago	Region M. De Santiago
Colombia	Fundación Valle del Lili ( Site 1703)	Cali	Valle Del Cauca
France	Centre Hospitalier Universitaire Estaing ( Site 2105)	Clermont-Ferrand	Puy-de-Dome
France	CHD Vendee ( Site 2100)	La Roche-sur-Yon	Vendee
France	Hopital Claude Huriez - CHU de Lille ( Site 2107)	Lille	Nord
Germany	Universitätsklinikum Leipzig-Medical Department I - Hematology and Celltherapy ( Site 2201)	Leipzig	Sachsen
Germany	Klinikum Mutterhaus der Borromäerinnen-Innere Medizin I ( Site 2203)	Trier	Rheinland-Pfalz
Israel	Rambam Health Care Campus ( Site 2801)	Haifa
Israel	Hadassah Medical Center-Hemato-Oncology ( Site 2812)	Jerusalem
Israel	Sheba Medical Center-Hemato Oncology ( Site 2809)	Ramat Gan
Israel	Sourasky Medical Center ( Site 2811)	Tel Aviv
Italy	Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare -Azienda Ospedaliera Nazionale SS. Ant	Alessandria
Italy	Ospedale San Raffaele-Programma di Ricerca Strategica sulla LLC ( Site 2902)	Milano
Italy	Arcispedale Santa Maria Nuova-Hematology ( Site 2900)	Reggio Emilia
Puerto Rico	Auxilio Mutuo Cancer Center ( Site 3900)	San Juan
South Africa	Groote Schuur Hospital ( Site 4400)	Cape Town	Western Cape
South Africa	Haemalife ( Site 4407)	Kuilsriver	Western Cape
South Africa	Netcare Pretoria East Hospital-Albert Alberts Stem Cell Transplant Centre ( Site 4401)	Moreletta Park	Gauteng
Spain	Instituto Catalan de Oncologia - Hospital Duran i Reynals-Haematology Department ( Site 4601)	L'Hospitalet Del Llobregat	Barcelona
Spain	HOSPITAL UNIVERSITARIO QUIRONSALUD MADRID ( Site 4602)	Pozuelo de Alarcon	Madrid
Spain	HOSPITAL CLINICO DE VALENCIA-HEMATOLOGY ( Site 4603)	Valencia	Valenciana, Comunitat
United Kingdom	University College London Hospital-Cancer Clinical Trials Unit ( Site 5001)	London-Camden	London, City Of
United Kingdom	City Hospital, Nottingham University Hospitals-Hematology ( Site 5002)	Nottingham	England
United States	MemorialCare Health System - Long Beach Medical Center ( Site 5421)	Long Beach	California
United States	University of Wisconsin Hospital and Clinics-Carbone Cancer Center ( Site 5423)	Madison	Wisconsin
United States	Memorial Hospital West ( Site 5410)	Pembroke Pines	Florida
United States	Medical Oncology Associates, PS ( Site 5406)	Spokane	Washington
United States	Highlands Oncology Group ( Site 5405)	Springdale	Arkansas

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Chile,  Colombia,  France,  Germany,  Israel,  Italy,  Puerto Rico,  South Africa,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Up to approximately 12 Weeks
Primary	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
Primary	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
Primary	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	Part 2: Undetectable minimal residual disease (MRD) rate in bone marrow as assessed by central laboratory	Undetectable MRD, defined as <1 leukemic cell per 10,000 cells (MRD <10-4) in bone marrow. The MRD rate will be presented.	Month 14
Secondary	Part 2: Overall Survival (OS)	OS, defined as the time from randomization to death due to any cause. OS will be presented.	Up to approximately 108 months
Secondary	Part 2: Objective Response Rate (ORR) per iwCLL Criteria 2018 as assessed by BICR	OR, defined as complete response/remission (CR), complete response with incomplete count recovery (CRi), nodular partial remission (nPR), or partial remission (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. ORR will be presented.	Up to approximately 108 months
Secondary	Part 2: Duration of Response (DOR) per iwCLL Criteria 2018 as assessed by BICR	DOR, defined as the time from the first documented evidence of CR, CRi, nPR, or PR that led to response until disease progression or death due to any cause, whichever occurs first. 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. DOR will be presented.	Up to approximately 108 months
Secondary	Part 2: Number of participants experiencing 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 2.	Up to approximately 28 months
Secondary	Part 2: 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 2.	Up to approximately 25 months

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary