A Phase 2 Study to Evaluate the Efficacy and Safety of MK-1026 in Participants with Hematologic Malignancies

Phase 2

Recruiting

Conditions: Chronic lymphocytic leukemia/Small lymphocytic lymphoma; Richters transformation; Mantle cell lymphoma, Marginal zone lymphoma; Follicular lymphoma; Waldenström’s macroglobulinemia

Registration Number: 2023-504931-42-00

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 1. Part 1: To determine the safety and tolerability and to establish the RP2D of nemtabrutinib.

2. Part 2: Cohorts A to C and J (CLL/ SLL): To evaluate the ORR following administration with nemtabrutinib per iwCLL criteria 2018 as assessed by ICR.

3. Part 2: Cohorts D to G (RT, MCL, MZL, FL): To evaluate the ORR following administration with nemtabrutinib per the Lugano criteria 2014 as assessed by ICR.

4. Part 2: Cohort H (WM): To evaluate the ORR following administration with nemtabrutinib per IWWM 2014 as assessed by ICR.

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 238

Inclusion Criteria

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

Part 1 and Part 2 (Cohorts A to C and J) • Has a confirmed diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with o At least 2 lines of prior therapy (Part 1 only) o 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 o 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 o 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 o Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i o Has active disease for CLL/SLL clearly documented to initiate therapy o 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 meets the following prior therapy requirements: o Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D) o Participants with pathologically confirmed mantle-cell lymphoma (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) o Participants with marginal zone lymphoma (MZL) (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi (Cohort F) o Participants with follicular lymphoma (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 computed tomography (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 Waldenström’s macroglobulinemia (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); immunoglobulin M (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

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

Participants with human immunodeficiency virus (HIV) are eligible if they meet all of the following: the cluster of differentiation 4+ (CD4) count is >350 cells/uL at screening, the HIV viral load is below the detectable level, are on a stable antiretroviral therapy (ART) regimen for at least 4 weeks prior to study entry, and are compliant with their ART

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 stable disease (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

Study & Design

Study Type: Not specified

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)		Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)
Part 1: Number of participants experiencing adverse events (AEs)		Part 1: Number of participants experiencing adverse events (AEs)
Part 1: Number of participants discontinuing study treatment due to AEs		Part 1: Number of participants discontinuing study treatment due to AEs
Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)		Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)
Part 2: ORR per Lugano criteria 2014 as assessed by ICR		Part 2: ORR per Lugano criteria 2014 as assessed by ICR
Part 2: ORR per International Workshop on Waldenström’s Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR		Part 2: ORR per International Workshop on Waldenström’s Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR

Secondary Outcome Measures

Name	Time	Method
Part 1: Area Under the Curve (AUC) of nemtabrutinib		Part 1: Area Under the Curve (AUC) of nemtabrutinib
Part 1: Minimum Concentration (Cmin) of nemtabrutinib		Part 1: Minimum Concentration (Cmin) of nemtabrutinib
Part 1: Maximum Concentration (Cmax) of nemtabrutinib		Part 1: Maximum Concentration (Cmax) of nemtabrutinib
Part 1: ORR per iwCLL criteria 2018 as assessed by ICR		Part 1: ORR per iwCLL criteria 2018 as assessed by ICR
Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR		Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR
Part 2: Number of participants experiencing AEs		Part 2: Number of participants experiencing AEs
Part 2: Number of participants discontinuing study treatment due to AEs		Part 2: Number of participants discontinuing study treatment due to AEs
Part 2: AUC of nemtabrutinib		Part 2: AUC of nemtabrutinib
Part 2: Cmin of nemtabrutinib		Part 2: Cmin of nemtabrutinib
Part 2: Cmax of nemtabrutinib		Part 2: Cmax of nemtabrutinib
Part 2: DOR per iwCLL criteria 2018 as assessed by ICR		Part 2: DOR per iwCLL criteria 2018 as assessed by ICR
Part 2: DOR per Lugano criteria 2014 as assessed by ICR		Part 2: DOR per Lugano criteria 2014 as assessed by ICR
Part 2: DOR per IWWM criteria 2014 as assessed by ICR		Part 2: DOR per IWWM criteria 2014 as assessed by ICR

Trial Locations

Locations (38): Fakultni Nemocnice Hradec Kralove
🇨🇿
Novy Hradec Kralove, Czechia
Fakultni Nemocnice Brno
🇨🇿
Brno, Czechia
Technische Universitat Dresden
🇩🇪
Dresden, Germany
University Hospital Cologne AöR
🇩🇪
Cologne, Germany
Universitaetsklinikum Ulm AöR
🇩🇪
Ulm, Germany
Institut Catala D'oncologia
🇪🇸
L'hospitalet De Llobregat, Spain
Hospital General Universitario Dr. Balmis
🇪🇸
Alicante, Spain
Complexo Hospitalario Universitario A Coruna
🇪🇸
A Coruna, Spain
Hospital Universitario 12 De Octubre
🇪🇸
Madrid, Spain
Hospital Universitario De Salamanca
🇪🇸
Salamanca, Spain
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Fakultni Nemocnice Hradec Kralove
🇨🇿Novy Hradec Kralove, Czechia
David Belada
Site contact
+420495832159
David.Belada@fnhk.cz