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

Hematologic Malignancies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04728893
• Other study ID #: 1026-003
• Secondary ID: MK-1026-0032020-
• Status: Recruiting
• Phase: Phase 2
• Start date: April 5, 2021
• Est. completion date: March 19, 2027

Study information

• Verified date: June 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 490
• Est. completion date: March 19, 2027
• Est. primary completion date: March 19, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukaemia
• Hematologic Malignancies
• Hematologic Neoplasms
• Leukemia, Lymphocytic, Chronic, B-Cell
• Neoplasms
• Non-Hodgkins Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

Drug:
• Nemtabrutinib
Nemtabrutinib tablets administered PO QD.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Poland,  Romania,  Spain,  Switzerland,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)	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.	Up to ~56 days (Cycles 1-2, cycle = 28 days)
Primary	Part 1: Number of participants experiencing adverse events (AEs)	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.	Up to ~71 months
Primary	Part 1: Number of participants discontinuing study treatment due to AEs	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.	Up to ~42 months
Primary	Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)	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.	Up to ~61 months
Primary	Part 2: ORR per Lugano criteria 2014 as assessed by ICR	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.	Up to ~61 months
Primary	Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR	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).	Up to ~71 months
Secondary	Part 1: Area Under the Curve (AUC) of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 1: Minimum Concentration (Cmin) of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 1: Maximum Concentration (Cmax) of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 1: ORR per iwCLL criteria 2018 as assessed by ICR	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.	Up to ~71 months
Secondary	Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR	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.	Up to ~71 months
Secondary	Part 2: Number of participants experiencing AEs	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.	Up to ~61 months
Secondary	Part 2: Number of participants discontinuing study treatment due to AEs	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.	Up to ~42 months
Secondary	Part 2: AUC of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 2: Cmin of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 2: Cmax of Nemtabrutinib	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.	At designated time points (up to ~57 days)
Secondary	Part 2: DOR per iwCLL criteria 2018 as assessed by ICR	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.	Up to ~61 months
Secondary	Part 2: DOR per Lugano criteria 2014 as assessed by ICR	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.	Up to ~61 months
Secondary	Part 2: DOR per IWWM criteria 2014 as assessed by ICR	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).	Up to ~61 months

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