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

Official title

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

Overview

The purpose of this study is to evaluate the safety and efficacy of nemtabrutinib (formerly ARQ 531) in participants with hematologic malignancies of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), Richter's transformation, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia (WM).

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).

Interventions

• Drug Nemtabrutinib
  Nemtabrutinib tablets administered orally QD.

Primary outcome measures

• Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) [Time frame: Up to ~56 days (Cycles 1-2, cycle = 28 days)]
• Part 1: Number of participants experiencing adverse events (AEs) [Time frame: Up to ~71 months]
• Part 1: Number of participants discontinuing study treatment due to AEs [Time frame: Up to ~42 months]
• 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 ~61 months]
• Part 2: ORR per Lugano criteria 2014 as assessed by ICR [Time frame: Up to ~61 months]
• Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR [Time frame: Up to ~71 months]

Secondary outcome measures (12)

• Part 1: Area Under the Curve (AUC) of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 1: Minimum Concentration (Cmin) of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 1: Maximum Concentration (Cmax) of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 1: ORR per iwCLL criteria 2018 as assessed by ICR [Time frame: Up to ~71 months]
• Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR [Time frame: Up to ~71 months]
• Part 2: Number of participants experiencing AEs [Time frame: Up to ~61 months]
• Part 2: Number of participants discontinuing study treatment due to AEs [Time frame: Up to ~42 months]
• Part 2: AUC of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 2: Cmin of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 2: Cmax of Nemtabrutinib [Time frame: At designated time points (up to ~57 days)]
• Part 2: DOR per iwCLL criteria 2018 as assessed by ICR [Time frame: Up to ~61 months]
• Part 2: DOR per Lugano criteria 2014 as assessed by ICR [Time frame: Up to ~61 months]

Eligibility criteria

Inclusion criteria

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before C1D1 (the first dose of study treatment)
• 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 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 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 and J)

• Has a confirmed diagnosis of Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (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
• Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i. NOTE: As of Protocol Amendment 09, at least 10 CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi, BCL2i and noncovalent/reversible BTKi (all three classes of therapies are required) will be enrolled into Cohort J
• Has active disease for CLL/SLL clearly documented to initiate therapy
• For SLL participants in Part 2: 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:

• Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D)
• 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)
• Participants with Marginal zone lymphoma (MZL) (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to at least one prior line of systemic therapy including an anti-CD20-based regimen
• Participants with Follicular lymphoma (FL) who are relapsed or refractory to chemoimmunotherapy and immunomodulatory agents (such as lenalidomide based regimen) (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); 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 (e.g., 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 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before C1D1
• 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

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 19 centers

• Anhui Provincial Hospital ( Site 2808) — Hefei
• Peking University Third Hospital-Hematology ( Site 2827) — Beijing
• The Second Affiliated Hospital of Chongqing Medical University ( Site 2825) — Chongqing
• Sun Yat-sen University Cancer Center-Internal Medicine ( Site 2824) — Guangzhou
• Liuzhou People's Hospital ( Site 2817) — Liuzhou
• Guangxi Medical University Cancer Hospital ( Site 2814) — Nanning
• Henan Cancer Hospital-hematology department ( Site 2802) — Zhengzhou
• Wuhan Union Hospital ( Site 2816) — Wuhan
• … and 11 more centers

United States · 11 centers

• Highlands Oncology Group ( Site 2728) — Springdale
• University of California San Diego Moores Cancer Center ( Site 2717) — La Jolla
• Lundquist Institute for Biomedical Innovation at Harbor-UCLA-Hematology and Medical Oncolo — Torrance
• Colorado Blood Cancer Institute ( Site 2726) — Denver
• The University of Louisville, James Graham Brown Cancer Center ( Site 2729) — Louisville
• Mayo Clinic - Rochester ( Site 2706) — Rochester
• Astera Cancer Care ( Site 2732) — East Brunswick
• John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704) — Hackensack
• … and 3 more centers

Italy · 8 centers

• Istituto Tumori Giovanni Paolo II ( Site 1409) — Bari
• A.O. Universitaria Policlinico S. Orsola-Malpighi ( Site 1400) — Bologna
• ASST Spedali Civili di Brescia ( Site 1408) — Brescia
• IRCCS Ospedale San Raffaele ( Site 1402) — Milan
• Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1403) — Naples
• … and 3 more centers

United Kingdom · 8 centers

Center list to be confirmed — check the primary protocol.

Israel · 7 centers

• Ha Emek Medical Center ( Site 1305) — Afula
• Soroka Medical Center ( Site 1307) — Beersheba
• Rambam Medical Center ( Site 1301) — Haifa
• Hadassah Ein Karem Jerusalem ( Site 1300) — Jerusalem
• Chaim Sheba Medical Center ( Site 1302) — Ramat Gan
• Kaplan Medical Center ( Site 1304) — Rehovot
• Sourasky Medical Center ( Site 1303) — Tel Aviv

Spain · 7 centers

Center list to be confirmed — check the primary protocol.

Argentina · 6 centers

• Hospital Aleman ( Site 0102) — Ciudad Autonoma de Buenos Aires
• Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103) — Buenos Aires
• Fundacion Estudios Clinicos ( Site 0112) — Rosario
• FUNDALEU ( Site 0104) — Caba
• Hospital Privado Universitario de Córdoba ( Site 0107) — Córdoba
• Fundacion Centro Oncologico de Integración Regional-Medical Oncology ( Site 0110) — Mendoza

France · 5 centers

• Centre Hospitalier Universitaire de Nice - Hôpital l'Archet ( Site 0810) — Nice
• Centre Hospitalier Lyon-Sud ( Site 0804) — Pierre-Bénite
• Institut Paoli-Calmettes ( Site 0803) — Marseille
• Centre Hospitalier de Versailles ( Site 0809) — Le Chesnay
• Hopital Saint Louis ( Site 0805) — Paris

Poland · 5 centers

Center list to be confirmed — check the primary protocol.

Turkey (Türkiye) · 5 centers

Center list to be confirmed — check the primary protocol.

Brazil · 4 centers

• Hospital das Clinicas FMUSP-Pesquisa Clínica Hematologia ( Site 0303) — São Paulo
• Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0300) — Rio de Janeiro
• BP - A Beneficencia Portuguesa de São Paulo ( Site 0302) — São Paulo
• Hospital Paulistano - Amil Clinical Research ( Site 0311) — São Paulo

Canada · 4 centers

• Arthur J.E. Child Comprehensive Cancer Centre ( Site 0401) — Calgary
• The Ottawa Hospital ( Site 0404) — Ottawa
• Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406) — Toronto
• CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0403) — Montreal

Denmark · 4 centers

• Aarhus University Hospital ( Site 0702) — Aarhus N
• Aalborg Universitetshospital ( Site 0703) — Aalborg
• Sjaellands Universitetshospital Roskilde ( Site 0701) — Roskilde
• Odense University Hospital ( Site 0705) — Odense C

Germany · 4 centers

• Universitaetsklinikum Ulm. ( Site 0906) — Ulm
• Universitaetsklinikum Koeln ( Site 0901) — Cologne
• St. Marien-Krankenhaus Siegen ( Site 0914) — Siegen
• Universitaetsklinikum Carl Gustav Carus ( Site 0902) — Dresden

Hungary · 4 centers

• Pecsi Tudomanyegyetem Altalanos Orvostudomanyi Kar ( Site 1202) — Pécs
• Debreceni Egyetem Klinikai Kozpont ( Site 1201) — Debrecen
• Szabolcs Szatmár Bereg Vármegyei Oktatókórház ( Site 1206) — Nyíregyháza
• Orszagos Onkologiai Intezet ( Site 1200) — Budapest

Romania · 4 centers

Center list to be confirmed — check the primary protocol.

Ukraine · 4 centers

Center list to be confirmed — check the primary protocol.

Australia · 3 centers

• Nepean Hospital-Nepean Cancer Care Centre ( Site 0204) — Sydney
• Box Hill Hospital ( Site 0203) — Box Hill
• Sir Charles Gairdner Hospital ( Site 0200) — Nedlands

Czechia · 2 centers

• Fakultní nemocnice Brno Bohunice-Interni hematologicka a onkologicka klinika ( Site 0600) — Brno
• Fakultni nemocnice Hradec Kralove ( Site 0601) — Hradec Králové

Ireland · 2 centers

• Beaumont Hospital ( Site 2900) — Dublin
• University Hospital Limerick ( Site 2903) — Limerick

South Korea · 2 centers

Center list to be confirmed — check the primary protocol.

Switzerland · 2 centers

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT04728893 · 1026-003 · MK-1026-003 · 2023-504931-42-00 · U1111-1290-4004 · 2020-002324-36

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗