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)

Overview

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).

Interventions

• Drug Nemtabrutinib
  5, 20, and 45 tablets
• Drug Venetoclax
  10, 50, and 100 mg tablets
• Biological Rituximab
  100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Primary outcome measures

• Part 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) [Time frame: Up to approximately 12 Weeks]
• Part 1: Number of Participants Experiencing Adverse Events (AEs) [Time frame: Up to approximately 28 months]
• Part 1: Number of Participants Discontinuing Study Treatment Due to AEs [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) [Time frame: Up to approximately 71 months]

Secondary outcome measures (6)

• 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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 10 centers

• Highlands Oncology Group ( Site 5405) — Springdale
• MemorialCare Health System - Long Beach Medical Center ( Site 5421) — Long Beach
• Memorial Hospital West ( Site 5410) — Pembroke Pines
• Fort Wayne Medical Oncology and Hematology ( Site 5444) — Fort Wayne
• Center for Cancer and Blood Disorders ( Site 5439) — Bethesda
• Hattiesburg Clinic Hematology/Oncology ( Site 5416) — Hattiesburg
• Oregon Health and Science University ( Site 5425) — Portland
• Vista Oncology ( Site 5449) — Olympia
• … and 2 more centers

Argentina · 6 centers

• Instituto Alexander Fleming ( Site 1005) — Ciudad Autónoma de Buenos Aires
• Instituto de Investigaciones Clínicas Mar del Plata ( Site 1007) — Mar del Plata
• Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Hematology ( Site 1002) — Buenos Aires
• Sanatorio Parque ( Site 1003) — Rosario
• Centro Medico Fleischer ( Site 1006) — Buenos Aires
• Hospital Aleman-oncohematologic diseases ( Site 1001) — Buenos Aires

Chile · 5 centers

• Biocenter ( Site 1507) — Concepción
• IC La Serena Research ( Site 1506) — La Serena
• Centro de Estudios Clínicos SAGA-CECSAGA ( Site 1509) — Santiago
• FALP-UIDO ( Site 1500) — Santiago
• Clínica Inmunocel ( Site 1511) — Santiago

Turkey (Türkiye) · 5 centers

• Ege Universitesi Hastanesi ( Site 4902) — Bornova
• Namik Kemal University Medical Faculty-Hematology ( Site 4912) — Tekirdağ
• Ankara Universitesi Tip Fakultesi Hastanesi-hematology ( Site 4913) — Ankara
• Mega Medipol-Hematology ( Site 4904) — Istanbul
• TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi ( Site 4906) — Istanbul

Israel · 4 centers

• Rambam Health Care Campus ( Site 2801) — Haifa
• Hadassah Medical Center-Hemato-Oncology ( Site 2812) — Jerusalem
• Sheba Medical Center-Hemato Oncology ( Site 2809) — Ramat Gan
• Sourasky Medical Center ( Site 2811) — Tel Aviv

Canada · 3 centers

• The Moncton Hospital ( Site 1414) — Moncton
• Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre ( Site 1402) — Greenfield Park
• Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospital — Sherbrooke

France · 3 centers

• Hopital Claude Huriez - CHU de Lille ( Site 2107) — Lille
• Centre Hospitalier Universitaire Estaing ( Site 2105) — Clermont-Ferrand
• CHD Vendee ( Site 2100) — La Roche-sur-Yon

Italy · 3 centers

• Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e Cesare Arrigo ( Site 2906) — Alessandria
• Ospedale San Raffaele-Programma di Ricerca Strategica sulla LLC ( Site 2902) — Milan
• Arcispedale Santa Maria Nuova-Hematology ( Site 2900) — Reggio Emilia

Mexico · 3 centers

• Centro de Infusion Superare ( Site 3314) — Mexico City
• Health Pharma Professional Research S.A. de C.V: ( Site 3301) — Mexico City
• Centro de Investigacion Clinica Chapultepec ( Site 3309) — Morelia

South Africa · 3 centers

• Alberts Cellular Therapy. ( Site 4401) — Pretoria
• Groote Schuur Hospital ( Site 4400) — Cape Town
• Haemalife ( Site 4407) — Kuilsriver

Spain · 3 centers

• Instituto Catalan de Oncologia - Hospital Duran i Reynals-Haematology Department ( Site 46 — L'Hospitalet Del Llobregat
• HOSPITAL UNIVERSITARIO QUIRONSALUD MADRID ( Site 4602) — Pozuelo de Alarcón
• HOSPITAL CLINICO DE VALENCIA-HEMATOLOGY ( Site 4603) — Valencia

Australia · 2 centers

• Royal Adelaide Hospital ( Site 1104) — Adelaide
• Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103) — Melbourne

Belgium · 2 centers

• UZ Leuven-Hematology ( Site 1200) — Leuven
• ZAS Cadix ( Site 1203) — Antwerp

Germany · 2 centers

• Klinikum Mutterhaus der Borromäerinnen-Innere Medizin I ( Site 2203) — Trier
• Universitätsklinikum Leipzig-Medical Department I - Hematology and Celltherapy ( Site 2201 — Leipzig

United Kingdom · 2 centers

• City Hospital, Nottingham University Hospitals-Hematology ( Site 5002) — Nottingham
• University College London Hospital-Cancer Clinical Trials Unit ( Site 5001) — London-Camden

Brazil · 1 center

• ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308) — São Paulo

Colombia · 1 center

• Fundación Valle del Lili ( Site 1703) — Cali

Puerto Rico · 1 center

• Auxilio Mutuo Cancer Center ( Site 3900) — San Juan

Identifiers

NCT: NCT05947851 · 1026-010 · MK-1026-010 · BELLWAVE-010 · 2022-501560-17-00 · U1111-1281-1520 · jRCT2061260028

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗