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JOURNAL ONKOLOGIE – STUDIE

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)

Rekrutierend

NCT-Nummer:
NCT05947851

Studienbeginn:
August 2023

Letztes Update:
25.04.2024

Wirkstoff:
Nemtabrutinib, Venetoclax, Rituximab

Indikation (Clinical Trials):
Lymphoma, Leukemia, Leukemia, Lymphoid, Leukemia, Lymphocytic, Chronic, B-Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Merck Sharp & Dohme LLC

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme LLC

Kontakt

Studienlocations
(3 von 42)

Klinikum Mutterhaus der Borromäerinnen-Innere Medizin I ( Site 2203)
54290 Trier
(Rheinland-Pfalz)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 0049 651 947 2571» Ansprechpartner anzeigen
Universitätsklinikum Leipzig-Medical Department I - Hematology and Celltherapy ( Site 2201)
04103 Leipzig
(Sachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 03419713858» Ansprechpartner anzeigen
Centro de Educación Médica e Investigaciones Clínicas (CEMIC)-Hematology ( Site 1002)
C1431FWO Buenos Aires
ArgentinaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +5491159785130» Ansprechpartner anzeigen
Western Health-Sunshine & Footscray Hospitals-Cancer Services-Cancer Research ( Site 1103)
3021 Melbourne
AustraliaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 61395944044» Ansprechpartner anzeigen
ICESP - INSTITUTO DO CÂNCER DO ESTADO DE SÃO PAULO-Pesquisa Clinica ( Site 1308)
01246-000 São Paulo
BrazilRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +5511999014316» Ansprechpartner anzeigen
Centre intégré universitaire de santé et de services sociaux de l'Estrie - Centre Hospitalier Univer
J1H 5H3 Sherbrooke
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 819-346-1110 ext 12811» Ansprechpartner anzeigen
Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare -Azienda Ospedaliera Nazionale SS. Ant
15121 Alessandria
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +390131206440» Ansprechpartner anzeigen
Netcare Pretoria East Hospital-Albert Alberts Stem Cell Transplant Centre ( Site 4401)
0181 Moreletta Park
South AfricaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 27129932555» Ansprechpartner anzeigen
Instituto Catalan de Oncologia - Hospital Duran i Reynals-Haematology Department ( Site 4601)
08908 L'Hospitalet Del Llobregat
SpainRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +34932607750» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) (Time Frame - 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.

2. Part 1: Number of participants experiencing adverse events (AEs) (Time Frame - 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.

3. Part 1: Number of participants discontinuing study treatment due to AEs (Time Frame - 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.

4. 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):
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.

Secondary outcome:

1. Part 2: Undetectable minimal residual disease (MRD) rate in bone marrow as assessed by central laboratory (Time Frame - Month 14):
Undetectable MRD, defined as <1 leukemic cell per 10,000 cells (MRD <10-4) in bone marrow. The MRD rate will be presented.

2. Part 2: Overall Survival (OS) (Time Frame - Up to approximately 108 months):
OS, defined as the time from randomization to death due to any cause. OS will be presented.

3. Part 2: Objective Response Rate (ORR) per iwCLL Criteria 2018 as assessed by BICR (Time Frame - Up to approximately 108 months):
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.

4. Part 2: Duration of Response (DOR) per iwCLL Criteria 2018 as assessed by BICR (Time Frame - Up to approximately 108 months):
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.

5. Part 2: Number of participants experiencing AEs (Time Frame - 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 2.

6. Part 2: Number of participants discontinuing study treatment due to AEs (Time Frame - 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 2.

Studien-Arme

  • Experimental: Nemtabrutinib + Venetoclax
    Participants will receive nemtrabrutinib oral tablets at specified doses daily starting at Cycle 1 Day 1 (C1D1) and venetoclax oral tablets at doses of 20 mg up to 400 mg daily starting at Cycle 2 Day 1 (C2D1) up to 2 years post C2D1 or until progressive disease (PD) or discontinuation. A cycle = 4 weeks.
  • Active Comparator: Venetoclax + Rituximab
    Participants will receive venetoclax oral tablets at doses from 20 mg up to 400 mg daily starting at C1D1 on 4-week cycles up to 2 years and rituximab or biosimilar at 375 mg/m^2 up to 500 mg/m2 intravenous infusion once per 28-day cycle starting at C2D1, for 6 total cycles. Treatment will continue until progressive disease (PD) or discontinuation.

Geprüfte Regime

  • Nemtabrutinib (ARQ 531 / MK-1026 / ):
    5 and 20 mg tablets
  • Venetoclax (ABT-199 / GDC-0199 / ):
    10, 50, and 100 mg tablets
  • Rituximab:
    100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Quelle: ClinicalTrials.gov


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