Montag, 29. April 2024
Navigation öffnen
Anzeige:
Wefra Programatic
 
JOURNAL ONKOLOGIE – STUDIE

Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)

Rekrutierend

NCT-Nummer:
NCT04728893

Studienbeginn:
April 2021

Letztes Update:
11.04.2024

Wirkstoff:
Nemtabrutinib

Indikation (Clinical Trials):
Neoplasms, Hematologic Neoplasms, Leukemia, Lymphocytic, Chronic, B-Cell, Waldenstrom Macroglobulinemia

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Merck Sharp & Dohme LLC

Collaborator:
-

Studienleiter

Medical Director
Study Director
Merck Sharp & Dohme LLC

Kontakt

Studienlocations
(3 von 118)

St. Marien-Krankenhaus Siegen ( Site 0914)
57072 Siegen
(Nordrhein-Westfalen)
GermanyAbgeschlossen» Google-Maps
Lundquist Institute for Biomedical Innovation at Harbor-UCLA-Hematology and Medical Oncology ( Site
90502 Torrance
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 424-201-3000» Ansprechpartner anzeigen
John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704)
07601 Hackensack
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 551-996-3003» Ansprechpartner anzeigen
Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103)
C1431FWO Buenos Aires
ArgentinaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +541152990247» Ansprechpartner anzeigen
Fundacion Centro Oncologico de Integración Regional-Medical Oncology ( Site 0110)
M5500AYB Mendoza
ArgentinaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +54261-4252575» Ansprechpartner anzeigen
BP - A Beneficencia Portuguesa de São Paulo ( Site 0302)
01321-001 Sao Paulo
BrazilAktiv, nicht rekrutierend» Google-Maps
Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406)
M5G 2M9 Toronto
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 416-946-2827» Ansprechpartner anzeigen
Fakultní nemocnice Brno Bohunice-Interni hematologicka a onkologicka klinika ( Site 0600)
62500 Brno
CzechiaRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +420532233642» Ansprechpartner anzeigen
Odense University Hospital ( Site 0705)
5000 Odense C
DenmarkAbgeschlossen» Google-Maps
Uniwersytecki Szpital Kliniczny-Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku ( Site
50-367 Wroclaw
PolandRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +48717842576» Ansprechpartner anzeigen
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Kilinka Onkologii I Hematologii ( Site
02-781 Warszawa
PolandRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: 48225462366» Ansprechpartner anzeigen
Szpital Wojewódzki w Opolu-Hematology Department ( Site 1607)
45-061 Opole
PolandAbgeschlossen» Google-Maps
Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 2000)
08908 Hospitalet de Llobregat
SpainRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +34932607750» Ansprechpartner anzeigen
VKV Amerikan Hastanesi ( Site 2403)
34365 Istanbul
TurkeyAbgeschlossen» Google-Maps
MNPE ClinCenter of Oncology,Hematology,Transplantology and Palliative Care of CherkasyRegCouncil ( S
18009 Cherkassy
UkraineRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +380634253209» Ansprechpartner anzeigen
Nottingham University Hospitals NHS Trust. City Hospital Campus ( Site 2601)
NG5 1PF Nottingham
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Study Coordinator
Phone: +441159691169» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

This study will be performed in 2 parts: Dose Escalation and Confirmation (Part 1) and Cohort

Expansion (Part 2). Following determination of the recommended phase 2 dose (RP2D) in Part 1,

the study plans to proceed with Part 2 using 8 disease-specific expansion cohorts (Cohorts A

to H).

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7

days prior to allocation

- Has a life expectancy of at least 3 months, based on the investigator assessment

- 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 viral load prior to randomization

- Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV

viral load is undetectable at screening

- Has adequate organ function

- Male participants agree to refrain from donating sperm and agree to either remain

abstinent from penile-vaginal intercourse as their preferred and usual lifestyle OR

agree to use contraception, during the intervention period and for at least the time

required to eliminate the study intervention after last dose of study intervention

- Female participants assigned female sex at birth who are not pregnant or breastfeeding

are eligible to participate if not a participant of childbearing potential (POCBP), or

if a POCBP they either use a contraceptive method that is highly effective OR remain

abstinent from penile-vaginal intercourse as their preferred and usual lifestyle

during the intervention period and for at least 30 days after the last dose of study

intervention

- Participants with HIV are eligible if they meet all of the following: the CD4 count is

>350 cells/uL at screening, the HIV viral load is below the detectable level, are on a

stable ART regimen for at least 4 weeks prior to study entry, and are compliant with

their ART

Part 1 and Part 2 (Cohorts A to C)

- Has a confirmed diagnosis of CLL/SLL with

- At least 2 lines of prior therapy (Part 1 only)

- Part 2 Cohort A: CLL/SLL participants who are relapsed or refractory to prior

therapy with a covalent, irreversible Bruton's tyrosine kinase inhibitor (BTKi),

and a B-cell lymphoma 2 inhibitor (BCL2i). CLL participants must have received

and failed, been intolerant to, or determined by their treating physician to be a

poor phosphoinositide 3-kinase inhibitor (PI3Ki) candidate or ineligible for a

PI3Ki per local guidelines

- Part 2 Cohort B: CLL/SLL participants who are relapsed or refractory following at

least 1 line of prior therapy and are BTKi treatment naive

- Part 2 Cohort C: CLL/SLL participants with 17p deletion or tumor protein p53

(TP53) mutation who are relapsed or refractory following at least 1 line of prior

therapy

- Has active disease for CLL/SLL clearly documented to initiate therapy

- Has evaluable core or excisional lymph node biopsy for biomarker analysis from an

archival or newly obtained biopsy or bone marrow aspirate at Screening (optional

for participants enrolling in Part 1)

Part 2 (Cohorts D to G)

- Has a confirmed diagnosis of and response to previous treatment of one of the

following:

- Participants with Richter's transformation who are relapsed or refractory

following at least 1 line of prior therapy (Cohort D)

- Participants with pathologically confirmed MCL, documented by either

overexpression of cyclin D1 or t(11;14), who are relapsed or are refractory to

chemoimmunotherapy and a covalent irreversible BTKi (Cohort E)

- Participants with MZL (including splenic, nodal, and extra nodal MZL) who are

relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi

(Cohort F)

- Participants with FL who are relapsed or refractory to chemoimmunotherapy,

immunomodulatory agents (i.e. lenalidomide plus rituximab) (Cohort G)

- Have measurable disease defined as at least 1 lesion that can be accurately measured

in at least 2 dimensions with spiral CT scan

- Has a lymph node biopsy for biomarker analysis from an archival or newly obtained

biopsy or bone marrow aspirate (Cohort D) at Screening

Part 2 (Cohort H): confirmed diagnosis of WM; participants who are relapsed or refractory

to standard therapies for WM including chemoimmunotherapy and a covalent irreversible BTKi

- Has active disease defined as 1 of the following: systemic symptoms, physical

findings, laboratory abnormalities, coexisting disease

- Has measurable disease, satisfying any of the following: at least 1 lesion that can be

accurately measured in at least 2 dimensions with spiral CT scan (minimum measurement

must be >15 mm in the longest diameter or >10 mm in the short axis); IgM ≥450 mg/dL;

or bone marrow infiltration of 10%

- Has fresh bone marrow aspirate or a lymph node biopsy for biomarker analysis at

Screening or a lymph node biopsy from an archival

Exclusion Criteria:

- Has active HBV/HCV infection (Part 1 and Part 2)

- Has a history of malignancy ≤3 years before providing documented informed consent.

Participants with basal cell carcinoma of skin, squamous cell carcinoma of skin, or

carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone

potential curative therapy are not excluded. Participants with low-risk, early-stage

prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen <10 ng/mL)

either treated with definitive intent or untreated in active surveillance with SD are

not excluded

- Has active central nervous system (CNS) disease

- Has an active infection requiring systemic therapy

- Has received prior systemic anti-cancer therapy within 4 weeks prior to allocation

- Is currently participating in or has participated in a study of an investigational

agent or has used an investigational device within 4 weeks prior to the first dose of

study intervention

- Has any clinically significant gastrointestinal abnormalities that might alter

absorption

- History of severe bleeding disorders

Studien-Rationale

Primary outcome:

1. Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) (Time Frame - Up to ~56 days (Cycles 1-2, cycle = 28 days)):
DLTs will be defined as toxicities observed during the first 2 cycles (8 weeks) of Part 1 and include: 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 doses as a result of drug-related adverse events (AEs) during the first 2 cycles (8 weeks); Grade 5 toxicity.

2. Part 1: Number of participants experiencing adverse events (AEs) (Time Frame - Up to ~34 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 ~34 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 an AE will be reported for Part 1.

4. Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR) (Time Frame - Up to ~78 months):
ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (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.

5. Part 2: ORR per Lugano criteria 2014 as assessed by ICR (Time Frame - Up to ~78 months):
ORR per Lugano criteria 2014 is defined as the percentage of participants achieving a CR or PR. CR defined as EITHER CR by imaging (computed tomography [CT]): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR complete metabolic response (CMR): score of 1, 2 or 3 on the 5-point scale assessing fluorodeoxyglucose (FDG) metabolic activity in lymphomatous lesions (ranging from 1=no uptake above background to 5=uptake markedly higher than liver) AND bone marrow (BM) normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the sum of the product of diameters [SPD] of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR Partial Metabolic Response (PMR) with score of 4 or 5 on the FDG 5-point scale (with no new lesions) and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities.

6. Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR (Time Frame - Up to ~78 months):
ORR per IWWM criteria 2014 is defined as the percentage of participants achieving a CR, very good partial response (VGPR), or PR. CR is defined as all lymph nodes are normal in size (none ≥15 mm), liver and spleen normal in size, serum immunoglobulin M (IgM) values in the normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with a second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal), and ≥90% decrease from baseline in serum IgM, or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in serum IgM, and ≥50% decrease from baseline in the abnormal portion of the spleen (if previously abnormal).

Secondary outcome:

1. Part 1: Area Under the Curve (AUC) of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib AUC (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days.

2. Part 1: Minimum Concentration (Cmin) of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib Cmin (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days.

3. Part 1: Maximum Concentration (Cmax) of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 1 for the assessment of nemtabrutinib Cmax (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days.

4. Part 1: ORR per iwCLL criteria 2018 as assessed by ICR (Time Frame - Up to ~34 months):
ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a CR, CRi, nPR, or 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.

5. Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR (Time Frame - Up to ~34 months):
For participants with CR, CRi, nPR, or PR per iwCLL 2018 criteria, DOR is defined as the time from the first documented evidence of objective response until PD 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.

6. Part 2: Number of participants experiencing AEs (Time Frame - Up to ~78 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.

7. Part 2: Number of participants discontinuing study treatment due to AEs (Time Frame - Up to ~78 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 an AE will be reported for Part 2.

8. Part 2: AUC of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib AUC (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days.

9. Part 2: Cmin of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib Cmin (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days.

10. Part 2: Cmax of Nemtabrutinib (Time Frame - At designated time points (up to ~57 days)):
Blood samples will be obtained at designated time points during Part 2 for the assessment of nemtabrutinib Cmax (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days.

11. Part 2: DOR per iwCLL criteria 2018 as assessed by ICR (Time Frame - Up to ~78 months):
For participants with CR, CRi, nPR, or PR per iwCLL 2018 criteria, DOR is defined as the time from the first documented evidence of objective 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.

12. Part 2: DOR per Lugano criteria 2014 as assessed by ICR (Time Frame - Up to ~78 months):
For participants with CR or PR per Lugano criteria 2014, DOR is defined as the time from the first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as EITHER CR by imaging (CT): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR CMR: score of 1, 2 or 3 on the 5-point scale assessing FDG metabolic activity in lymphomatous lesions (ranging from 1=no uptake above background to 5=uptake markedly higher than liver and/or new lesions) AND BM normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the SPD of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR PMR with score of 4 or 5 on the FDG 5-point scale (with no new lesions) and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities.

13. Part 2: DOR per IWWM criteria 2014 as assessed by ICR (Time Frame - Up to ~78 months):
For participants with CR, VGPR, or PR per IWWM criteria 2014, DOR defined as the time from first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as all lymph nodes normal in size (none ≥15 mm), liver and spleen normal in size, serum IgM values in normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal), and ≥90% decrease from baseline in serum IgM, or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in serum IgM, and ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal).

Geprüfte Regime

  • Nemtabrutinib (ARQ 531 / MK-1026 / ):
    Nemtabrutinib tablets administered PO QD.

Quelle: ClinicalTrials.gov


Sie können folgenden Inhalt einem Kollegen empfehlen:

"Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)"

Bitte tragen Sie auch die Absenderdaten vollständig ein, damit Sie der Empfänger erkennen kann.

Die mit (*) gekennzeichneten Angaben müssen eingetragen werden!

Die Verwendung Ihrer Daten für den Newsletter können Sie jederzeit mit Wirkung für die Zukunft gegenüber der MedtriX GmbH - Geschäftsbereich rs media widersprechen ohne dass Kosten entstehen. Nutzen Sie hierfür etwaige Abmeldelinks im Newsletter oder schreiben Sie eine E-Mail an: rgb-info[at]medtrix.group.