Clinical trial NCT05947851: 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).
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Chronic Lymphocytic
Small-Cell Lymphoma
Lymphoma, Small Lymphocytic
CLL
SLL
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2023-07-17
Enrollment: 720
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)
timeFrame: Up to approximately 12 Weeks
measure: Part 1: Number of participants experiencing adverse events (AEs)
timeFrame: Up to approximately 28 months
measure: Part 1: Number of participants discontinuing study treatment due to AEs
timeFrame: Up to approximately 25 months
measure: Part 2: PFS per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as assessed by Blinded Independent Central Review (BICR)
timeFrame: Up to approximately 71 months
Secondary outcomes:
measure: Part 2: Undetectable minimal residual disease (MRD) rate in bone marrow as assessed by central laboratory
timeFrame: Month 14
measure: Part 2: Overall Survival (OS)
timeFrame: Up to approximately 108 months
measure: Part 2: Objective Response Rate (ORR) per iwCLL Criteria 2018 as assessed by BICR
timeFrame: Up to approximately 108 months
measure: Part 2: Duration of Response (DOR) per iwCLL Criteria 2018 as assessed by BICR
timeFrame: Up to approximately 108 months
measure: Part 2: Number of participants experiencing AEs
timeFrame: Up to approximately 28 months
measure: Part 2: Number of participants discontinuing study treatment due to AEs
timeFrame: Up to approximately 25 months
Other outcomes:
Locations:
city: Springdale
country: United States
facility: Highlands Oncology Group ( Site 5405)
state: Arkansas
city: Long Beach
country: United States
facility: MemorialCare Health System - Long Beach Medical Center ( Site 5421)
state: California
city: Pembroke Pines
country: United States
facility: Memorial Hospital West ( Site 5410)
state: Florida
city: Portland
country: United States
facility: Oregon Health and Science University ( Site 5425)
state: Oregon
city: Spokane
country: United States
facility: Medical Oncology Associates, PS ( Site 5406)
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics-Carbone Cancer Center ( Site 5423)
state: Wisconsin
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: Instituto Alexander Fleming ( Site 1005)
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Instituto de Investigaciones Clínicas Mar del Plata ( Site 1007)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Hematology ( Site 1002)
state: Caba
city: Rosario
country: Argentina
facility: Sanatorio Parque ( Site 1003)
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Centro Medico Fleischer ( Site 1006)
city: Buenos Aires
country: Argentina
facility: Hospital Aleman-oncohematologic diseases ( Site 1001)
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital ( Site 1104)
state: South Australia
city: Melbourne
country: Australia
facility: Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103)
state: Victoria
city: Leuven
country: Belgium
facility: UZ Leuven-Hematology ( Site 1200)
state: Vlaams-Brabant
city: Antwerpen
country: Belgium
facility: ZAS Cadix ( Site 1203)
city: Sao Paulo
country: Brazil
facility: ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308)
city: Moncton
country: Canada
facility: The Moncton Hospital ( Site 1414)
state: New Brunswick
city: Greenfield Park
country: Canada
facility: Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre ( Site 1402)
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Univer ( Site 1410)
state: Quebec
city: Concepcion.
country: Chile
facility: Biocenter ( Site 1507)
state: Biobio
city: La Serena.
country: Chile
facility: IC La Serena Research ( Site 1506)
state: Coquimbo
city: Santiago.
country: Chile
facility: Centro de Estudios Clínicos SAGA-CECSAGA ( Site 1509)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 1500)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Clínica Inmunocel ( Site 1511)
state: Region M. De Santiago
city: Cali
country: Colombia
facility: Fundación Valle del Lili ( Site 1703)
state: Valle Del Cauca
city: Lille
country: France
facility: Hopital Claude Huriez - CHU de Lille ( Site 2107)
state: Nord
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire Estaing ( Site 2105)
state: Puy-de-Dome
city: La Roche-sur-Yon
country: France
facility: CHD Vendee ( Site 2100)
state: Vendee
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen-Innere Medizin I ( Site 2203)
state: Rheinland-Pfalz
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig-Medical Department I - Hematology and Celltherapy ( Site 2201)
state: Sachsen
city: Haifa
country: Israel
facility: Rambam Health Care Campus ( Site 2801)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Hemato-Oncology ( Site 2812)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center-Hemato Oncology ( Site 2809)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 2811)
city: Alessandria
country: Italy
facility: Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e Cesare Arrigo ( Site 2906)
state: Ancona
city: Milano
country: Italy
facility: Ospedale San Raffaele-Programma di Ricerca Strategica sulla LLC ( Site 2902)
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova-Hematology ( Site 2900)
city: Ciudad de México
country: Mexico
facility: Centro de Infusion Superare ( Site 3314)
state: Distrito Federal
city: Ciudad de México
country: Mexico
facility: Health Pharma Professional Research S.A. de C.V: ( Site 3301)
state: Distrito Federal
city: Morelia
country: Mexico
facility: Centro de Investigacion Clinica Chapultepec ( Site 3309)
state: Michoacan
city: San Juan
country: Puerto Rico
facility: Auxilio Mutuo Cancer Center ( Site 3900)
city: Moreletta Park
country: South Africa
facility: Netcare Pretoria East Hospital-Albert Alberts Stem Cell Transplant Centre ( Site 4401)
state: Gauteng
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital ( Site 4400)
state: Western Cape
city: Kuilsriver
country: South Africa
facility: Haemalife ( Site 4407)
state: Western Cape
city: L'Hospitalet Del Llobregat
country: Spain
facility: Instituto Catalan de Oncologia - Hospital Duran i Reynals-Haematology Department ( Site 4601)
state: Barcelona
city: Pozuelo de Alarcon
country: Spain
facility: HOSPITAL UNIVERSITARIO QUIRONSALUD MADRID ( Site 4602)
state: Madrid
city: Valencia
country: Spain
facility: HOSPITAL CLINICO DE VALENCIA-HEMATOLOGY ( Site 4603)
state: Valenciana, Comunitat
city: Tekirdag
country: Turkey
facility: Namik Kemal University Medical Faculty-Hematology ( Site 4912)
state: Tekirdas
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Hastanesi-hematology ( Site 4913)
city: İstanbul
country: Turkey
facility: Mega Medipol-Hematology ( Site 4904)
city: Istanbul
country: Turkey
facility: TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi ( Site 4906)
city: İzmir
country: Turkey
facility: Ege Universitesi Hastanesi ( Site 4902)
city: Nottingham
country: United Kingdom
facility: City Hospital, Nottingham University Hospitals-Hematology ( Site 5002)
state: England
city: London-Camden
country: United Kingdom
facility: University College London Hospital-Cancer Clinical Trials Unit ( Site 5001)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: