Clinical trial NCT04728893: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hematologic Malignancies
Waldenstroms Macroglobulinaemia
Non-Hodgkins Lymphoma
Chronic Lymphocytic Leukaemia
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-01-28
Enrollment: 490
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

Eligibility criteria: 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 to eliminate study intervention 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 and J)

* 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
  * Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i
  * 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 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 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

Primary outcomes:
measure: Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)
timeFrame: Up to ~56 days (Cycles 1-2, cycle = 28 days)
measure: Part 1: Number of participants experiencing adverse events (AEs)
timeFrame: Up to ~71 months
measure: Part 1: Number of participants discontinuing study treatment due to AEs
timeFrame: Up to ~42 months
measure: Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)
timeFrame: Up to ~61 months
measure: Part 2: ORR per Lugano criteria 2014 as assessed by ICR
timeFrame: Up to ~61 months
measure: Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR
timeFrame: Up to ~71 months
Secondary outcomes:
measure: Part 1: Area Under the Curve (AUC) of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 1: Minimum Concentration (Cmin) of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 1: Maximum Concentration (Cmax) of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 1: ORR per iwCLL criteria 2018 as assessed by ICR
timeFrame: Up to ~71 months
measure: Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR
timeFrame: Up to ~71 months
measure: Part 2: Number of participants experiencing AEs
timeFrame: Up to ~61 months
measure: Part 2: Number of participants discontinuing study treatment due to AEs
timeFrame: Up to ~42 months
measure: Part 2: AUC of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 2: Cmin of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 2: Cmax of Nemtabrutinib
timeFrame: At designated time points (up to ~57 days)
measure: Part 2: DOR per iwCLL criteria 2018 as assessed by ICR
timeFrame: Up to ~61 months
measure: Part 2: DOR per Lugano criteria 2014 as assessed by ICR
timeFrame: Up to ~61 months
measure: Part 2: DOR per IWWM criteria 2014 as assessed by ICR
timeFrame: Up to ~61 months
Other outcomes:
Locations:
city: Springdale
country: United States
facility: Highlands Oncology Group ( Site 2728)
state: Arkansas
city: La Jolla
country: United States
facility: University of California San Diego Moores Cancer Center ( Site 2717)
state: California
city: Torrance
country: United States
facility: Lundquist Institute for Biomedical Innovation at Harbor-UCLA-Hematology and Medical Oncology ( Site 2724)
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute ( Site 2726)
state: Colorado
city: Louisville
country: United States
facility: The University of Louisville, James Graham Brown Cancer Center ( Site 2729)
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic - Rochester ( Site 2706)
state: Minnesota
city: East Brunswick
country: United States
facility: Astera Cancer Care ( Site 2732)
state: New Jersey
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704)
state: New Jersey
city: Fargo
country: United States
facility: Sanford Fargo Medical Center-Roger Maris Cancer Center ( Site 2708)
state: North Dakota
city: Dallas
country: United States
facility: UT Southwestern-Harold C. Simmons Cancer Center ( Site 2730)
state: Texas
city: Spokane
country: United States
facility: Medical Oncology Associates (Summit Cancer Centers) ( Site 2710)
state: Washington
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Hospital Aleman ( Site 0102)
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103)
state: Caba
city: Rosario
country: Argentina
facility: Fundacion Estudios Clinicos ( Site 0112)
state: Santa Fe
city: Caba
country: Argentina
facility: FUNDALEU ( Site 0104)
city: Cordoba
country: Argentina
facility: Hospital Privado Universitario de Córdoba ( Site 0107)
city: Mendoza
country: Argentina
facility: Fundacion Centro Oncologico de Integración Regional-Medical Oncology ( Site 0110)
city: Sydney
country: Australia
facility: Nepean Hospital-Nepean Cancer Care Centre ( Site 0204)
state: New South Wales
city: Box Hill
country: Australia
facility: Box Hill Hospital ( Site 0203)
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital ( Site 0200)
state: Western Australia
city: São Paulo
country: Brazil
facility: Hospital das Clinicas FMUSP-Pesquisa Clínica Hematologia ( Site 0303)
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
facility: Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0300)
city: Sao Paulo
country: Brazil
facility: BP - A Beneficencia Portuguesa de São Paulo ( Site 0302)
city: Sao Paulo
country: Brazil
facility: Hospital Paulistano - Amil Clinical Research ( Site 0311)
city: Calgary
country: Canada
facility: Arthur J.E. Child Comprehensive Cancer Centre ( Site 0401)
state: Alberta
city: Ottawa
country: Canada
facility: The Ottawa Hospital ( Site 0404)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre-Division of Medical Oncology and Hematology ( Site 0406)
state: Ontario
city: Montreal
country: Canada
facility: CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0403)
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital ( Site 0400)
state: Quebec
city: Hefei
country: China
facility: Anhui Provincial Hospital ( Site 2808)
state: Anhui
city: Beijing
country: China
facility: Peking University Third Hospital-Hematology ( Site 2827)
state: Beijing
city: Chongqing
country: China
facility: The Second Affiliated Hospital of Chongqing Medical University ( Site 2825)
state: Chongqing
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center-Internal Medicine ( Site 2824)
state: Guangdong
city: Liuzhou
country: China
facility: Guangxi Medical University - Liuzhou Renmin Hospital ( Site 2817)
state: Guangxi
city: Nanning
country: China
facility: Guangxi Medical University Affiliated Tumor Hospital ( Site 2814)
state: Guangxi
city: Zhengzhou
country: China
facility: Henan Cancer Hospital-hematology department ( Site 2802)
state: Henan
city: Wuhan
country: China
facility: Wuhan Union Hospital ( Site 2816)
state: Hubei
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South University ( Site 2820)
state: Hunan
city: Changsha
country: China
facility: Hunan Cancer Hospital ( Site 2822)
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Province Hospital ( Site 2823)
state: Jiangsu
city: Xuzhou
country: China
facility: The Affiliated Hospital of Xuzhou Medical College ( Site 2818)
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 2815)
state: Jiangxi
city: Changchun
country: China
facility: The First Hospital of Jilin University-Hematology ( Site 2803)
state: Jilin
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center ( Site 2801)
state: Shanghai
city: Shanghai
country: China
facility: Huashan Hospital, Fudan University ( Site 2821)
state: Shanghai
city: Cheng Du
country: China
facility: West China Hospital Sichuan University ( Site 2810)
state: Sichuan
city: Tianjin
country: China
facility: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Unio ( Site 2800)
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University ( Site 2826)
state: Zhejiang
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno Bohunice-Interni hematologicka a onkologicka klinika ( Site 0600)
state: Brno-mesto
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove ( Site 0601)
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital ( Site 0702)
state: Midtjylland
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital ( Site 0703)
state: Nordjylland
city: Roskilde
country: Denmark
facility: Sjaellands Universitetshospital Roskilde ( Site 0701)
state: Sjaelland
city: Odense C
country: Denmark
facility: Odense University Hospital ( Site 0705)
state: Syddanmark
city: Nice
country: France
facility: Centre Hospitalier Universitaire de Nice - Hôpital l'Archet ( Site 0810)
state: Alpes-Maritimes
city: Marseille
country: France
facility: Institut Paoli-Calmettes ( Site 0803)
state: Bouches-du-Rhone
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon-Sud ( Site 0804)
state: Rhone-Alpes
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles ( Site 0809)
state: Yvelines
city: Paris
country: France
facility: Hopital Saint Louis ( Site 0805)
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm. ( Site 0906)
state: Baden-Wurttemberg
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln ( Site 0901)
state: Nordrhein-Westfalen
city: Siegen
country: Germany
facility: St. Marien-Krankenhaus Siegen ( Site 0914)
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus ( Site 0902)
state: Sachsen
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem Altalanos Orvostudomanyi Kar ( Site 1202)
state: Baranya
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont ( Site 1201)
state: Hajdu-Bihar
city: Nyiregyhaza
country: Hungary
facility: Szabolcs Szatmár Bereg Vármegyei Oktatókórház ( Site 1206)
state: Szabolcs-Szatmar-Bereg
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet ( Site 1200)
city: Dublin
country: Ireland
facility: Beaumont Hospital ( Site 2900)
city: Limerick
country: Ireland
facility: University Hospital Limerick ( Site 2903)
city: Afula
country: Israel
facility: Ha Emek Medical Center ( Site 1305)
city: Beer-Sheva
country: Israel
facility: Soroka Medical Center ( Site 1307)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 1301)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Jerusalem ( Site 1300)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 1302)
city: Rehovot
country: Israel
facility: Kaplan Medical Center ( Site 1304)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 1303)
city: Bari
country: Italy
facility: Istituto Tumori Giovanni Paolo II ( Site 1409)
city: Bologna
country: Italy
facility: A.O. Universitaria Policlinico S. Orsola-Malpighi ( Site 1400)
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia ( Site 1408)
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele ( Site 1402)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1403)
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo ( Site 1407)
city: Reggio Emilia
country: Italy
facility: IRCCS - Arcispedale Santa Maria Nuova ( Site 1405)
city: Roma
country: Italy
facility: Policlinico Umberto I ( Site 1404)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 2201)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 2200)
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny-Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku ( Site 1606)
state: Dolnoslaskie
city: Krakow
country: Poland
facility: Pratia MCM Krakow ( Site 1601)
state: Malopolskie
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Kilinka Onkologii I Hematologii ( Site 1608)
state: Mazowieckie
city: Opole
country: Poland
facility: Szpital Wojewódzki w Opolu-Hematology Department ( Site 1607)
state: Opolskie
city: Gdynia
country: Poland
facility: Szpitale Pomorskie Sp. z o.o. ( Site 1600)
state: Pomorskie
city: București
country: Romania
facility: Spitalul Clinic Colțea ( Site 1805)
state: Bucuresti
city: Ovidiu
country: Romania
facility: Ovidius Clinical Hospital ( Site 1804)
state: Constanta
city: Brasov
country: Romania
facility: Centrul de Diagnostic si Tratament Oncologic Brasov ( Site 1802)
city: Iasi
country: Romania
facility: Institutul Regional de Oncologie Iasi ( Site 1801)
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 2000)
state: Barcelona
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca ( Site 2002)
state: Castilla Y Leon
city: A Coruña
country: Spain
facility: CHUAC-Complejo Hospitalario Universitario A Coruña ( Site 2005)
state: La Coruna
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante ( Site 2007)
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron ( Site 2001)
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre ( Site 2003)
city: Bern
country: Switzerland
facility: Inselspital Bern ( Site 2303)
state: Berne
city: Bellinzona
country: Switzerland
facility: Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 2302)
state: Ticino
city: Stanbul
country: Turkey
facility: Mega Medipol-Hematology ( Site 2406)
state: Istanbul
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi Cebeci Hastanesi ( Site 2400)
city: Istanbul
country: Turkey
facility: VKV Amerikan Hastanesi ( Site 2403)
city: Istanbul
country: Turkey
facility: Sisli Florence Nightingale Hastanesi ( Site 2407)
city: Izmir
country: Turkey
facility: Dokuz Eylül Üniversitesi-Hematology ( Site 2402)
city: Cherkassy
country: Ukraine
facility: MNPE ClinCenter of Oncology,Hematology,Transplantology and Palliative Care of CherkasyRegCouncil ( Site 2509)
state: Cherkaska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: Communal non-profit enterprise "Regional clinical hospital o-Hematology Department ( Site 2510)
state: Ivano-Frankivska Oblast
city: Lviv
country: Ukraine
facility: Instit. of Blood Transfusion Medicine of the National Academy ( Site 2506)
state: Lvivska Oblast
city: Kyiv
country: Ukraine
facility: National Cancer Institute ( Site 2507)
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Hospital 9 ( Site 2502)
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre ( Site 2610)
state: Bristol, City Of
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust. City Hospital Campus ( Site 2601)
state: England
city: Windsor
country: United Kingdom
facility: GenesisCare - Windsor ( Site 2608)
state: England
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK ( Site 2612)
state: London, City Of
city: Oxford
country: United Kingdom
facility: GenesisCare - Oxford ( Site 2607)
state: Oxfordshire
city: Newmarket
country: United Kingdom
facility: GenesisCare - Cambridge ( Site 2611)
state: Suffolk
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust. ( Site 2606)
state: Surrey
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust ( Site 2602)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: