Recruiting
Phase 3
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).
Condition(s) studied
Leukemia, Lymphocytic, Chronic, B-CellLeukemia, Chronic LymphocyticSmall-Cell LymphomaLymphoma, Small LymphocyticCLLSLL
Investigational drug(s) / intervention(s)
NemtabrutinibVenetoclaxRituximab
Nemtabrutinib: 5, 20, and 45 tablets
Venetoclax: 10, 50, and 100 mg tablets
Rituximab: 100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion
Study 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
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
Primary outcome measure(s)
- Part 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) — Up to approximately 12 Weeks
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.
- Part 1: Number of Participants Experiencing Adverse Events (AEs) — Up to approximately 28 months
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.
- Part 1: Number of Participants Discontinuing Study Treatment Due to AEs — Up to approximately 25 months
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.
- Part 2: PFS per the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by Blinded Independent Central Review (BICR) — Up to approximately 71 months
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.
Trial sites (67)
| Facility | City | Region | Status |
| Highlands Oncology Group ( Site 5405) |
Springdale |
Arkansas |
Recruiting |
| MemorialCare Health System - Long Beach Medical Center ( Site 5421) |
Long Beach |
California |
Recruiting |
| Memorial Hospital West ( Site 5410) |
Pembroke Pines |
Florida |
Recruiting |
| Fort Wayne Medical Oncology and Hematology ( Site 5444) |
Fort Wayne |
Indiana |
Recruiting |
| Center for Cancer and Blood Disorders ( Site 5439) |
Bethesda |
Maryland |
Recruiting |
| Hattiesburg Clinic Hematology/Oncology ( Site 5416) |
Hattiesburg |
Mississippi |
Recruiting |
| MidAmerica Cancer Care, LLC ( Site 5426) |
Kansas City |
Missouri |
Recruiting |
| Intermountain Health St. Vincent Regional Hospital - Cancer Centers of Montana ( Site 5433) |
Billings |
Montana |
Recruiting |
| Renown Regional Medical Center-Renown Health Medical Oncology ( Site 5434) |
Reno |
Nevada |
Recruiting |
| New York Oncology Hematology, P.C. ( Site 5453) |
Albany |
New York |
Recruiting |
| Oregon Health and Science University ( Site 5425) |
Portland |
Oregon |
Recruiting |
| Avera Cancer Institute- Research ( Site 5437) |
Sioux Falls |
South Dakota |
Recruiting |
| PatientCare Clinical Research LLC ( Site 5435) |
Sugar Land |
Texas |
Recruiting |
| University of Virginia Cancer Center ( Site 5402) |
Charlottesville |
Virginia |
Recruiting |
| Vista Oncology ( Site 5449) |
Olympia |
Washington |
Recruiting |
| Medical Oncology Associates, PS ( Site 5406) |
Spokane |
Washington |
Recruiting |
| University of Wisconsin Hospital and Clinics-Carbone Cancer Center ( Site 5423) |
Madison |
Wisconsin |
Completed |
| Instituto Alexander Fleming ( Site 1005) |
Ciudad Autónoma de Buenos Aires |
Buenos Aires |
Recruiting |
| Instituto de Investigaciones Clínicas Mar del Plata ( Site 1007) |
Mar del Plata |
Buenos Aires |
Recruiting |
| Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Hematology ( Site 1002) |
Buenos Aires |
Buenos Aires F.D. |
Recruiting |
| Sanatorio Parque ( Site 1003) |
Rosario |
Santa Fe Province |
Recruiting |
| Centro Medico Fleischer ( Site 1006) |
Buenos Aires |
Argentina |
Recruiting |
| Hospital Aleman-oncohematologic diseases ( Site 1001) |
Buenos Aires |
Argentina |
Recruiting |
| Royal Adelaide Hospital ( Site 1104) |
Adelaide |
South Australia |
Recruiting |
| Box Hill Hospital ( Site 1106) |
Box Hill |
Victoria |
Recruiting |
| Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103) |
Melbourne |
Victoria |
Recruiting |
| UZ Leuven-Hematology ( Site 1200) |
Leuven |
Vlaams-Brabant |
Recruiting |
| ZAS Cadix ( Site 1203) |
Antwerp |
Belgium |
Recruiting |
| ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308) |
São Paulo |
Brazil |
Active Not Recruiting |
| The Moncton Hospital ( Site 1414) |
Moncton |
New Brunswick |
Recruiting |
| Centre Intégré de Santé et de Services Sociaux de la Montérégie-Centre ( Site 1402) |
Greenfield Park |
Quebec |
Recruiting |
| Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Univer ( Site 1410) |
Sherbrooke |
Quebec |
Recruiting |
| Biocenter ( Site 1507) |
Concepción |
Biobio |
Recruiting |
| IC La Serena Research ( Site 1506) |
La Serena |
Coquimbo Region |
Recruiting |
| Centro de Estudios Clínicos SAGA-CECSAGA ( Site 1509) |
Santiago |
Region M. de Santiago |
Recruiting |
| FALP-UIDO ( Site 1500) |
Santiago |
Region M. de Santiago |
Recruiting |
| Clínica Inmunocel ( Site 1511) |
Santiago |
Region M. de Santiago |
Recruiting |
| Fundación Valle del Lili ( Site 1703) |
Cali |
Valle del Cauca Department |
Recruiting |
| Hopital Claude Huriez - CHU de Lille ( Site 2107) |
Lille |
Nord |
Recruiting |
| Centre Hospitalier Universitaire Estaing ( Site 2105) |
Clermont-Ferrand |
Puy-de-Dome |
Recruiting |
+ 27 more sites — see the full list on the official registry below.