Efficacy and Safety of Nemtabrutinib (MK-1026) in Participants With Hematologic Malignancies (MK-1026-003)
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This study will be performed in 2 parts: Dose Escalation and Confirmation (Part 1) and Cohort Expansion (Part 2). Following determination of a 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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Nemtabrutinib Participants receive nemtabrutinib orally once daily (QD) until progressive disease (PD) or discontinuation. |
Drug: Nemtabrutinib
Nemtabrutinib tablets administered PO QD.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) [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.
- Part 1: Number of participants experiencing adverse events (AEs) [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 1.
- Part 1: Number of participants discontinuing study treatment due to AEs [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 1.
- Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR) [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.
- Part 2: ORR per Lugano criteria 2014 as assessed by ICR [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.
- Part 2: ORR per International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR [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 Measures
- Part 1: Area Under the Curve (AUC) of Nemtabrutinib [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.
- Part 1: Minimum Concentration (Cmin) of Nemtabrutinib [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.
- Part 1: Maximum Concentration (Cmax) of Nemtabrutinib [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.
- Part 1: ORR per iwCLL criteria 2018 as assessed by ICR [Up to ~78 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.
- Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR [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 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.
- Part 2: Number of participants experiencing AEs [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.
- Part 2: Number of participants discontinuing study treatment due to AEs [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.
- Part 2: AUC of Nemtabrutinib [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.
- Part 2: Cmin of Nemtabrutinib [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.
- Part 2: Cmax of Nemtabrutinib [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.
- Part 2: DOR per iwCLL criteria 2018 as assessed by ICR [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.
- Part 2: DOR per Lugano criteria 2014 as assessed by ICR [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.
- Part 2: DOR per IWWM criteria 2014 as assessed by ICR [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).
Eligibility Criteria
Criteria
Inclusion Criteria:
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Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days prior to allocation
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Has a life expectancy of at least 3 months, based on the investigator assessment
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Has the ability to swallow and retain oral medication
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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
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Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
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Has adequate organ function
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Male participants agree to refrain from donating sperm and agree to either remain abstinent from heterosexual intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for 12 days after last dose of study intervention
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Female participants not pregnant or breastfeeding are eligible to participate if not a woman of childbearing potential (WOCBP), or if a WOCBP they either use a contraceptive method that is highly effective OR remain abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 30 days after the last dose of study intervention
Part 1 and Part 2 (Cohorts A to C and Cohort I)
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Has a confirmed diagnosis of CLL/SLL
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Has active disease for CLL/SLL clearly documented to initiate therapy
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Has evaluable core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy at Screening (optional for participants enrolling in Part 1)
Part 2 (Cohorts D to G)
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Has a confirmed diagnosis of and response to previous treatment of one of the following:
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Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D)
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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 BTK inhibitor (BTKi) (Cohort E)
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Participants with MZL (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi (Cohort F)
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Participants with FL who are relapsed or refractory to chemoimmunotherapy, immunomodulatory agents (i.e. lenalidomide plus rituximab) (Cohort G)
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Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan
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Has a lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy 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
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Has active disease defined as 1 of the following: systemic symptoms, physical findings, laboratory abnormalities, coexisting disease
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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%
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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:
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Has active HBV/HCV infection (Part 1 and Part 2)
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Has a history of malignancy ≤3 years prior to providing documented informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
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Has active central nervous system (CNS) disease
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Has an active infection requiring systemic therapy
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Has a known history of human immunodeficiency virus (HIV) infection
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Has received prior systemic anti-cancer therapy within 4 weeks prior to allocation
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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
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Has any clinically significant gastrointestinal abnormalities that might alter absorption
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | John Theurer Cancer Center at Hackensack University Medical Center ( Site 2704) | Hackensack | New Jersey | United States | 07601 |
| 2 | Medical Oncology Associates (Summit Cancer Centers) ( Site 2710) | Spokane | Washington | United States | 99208 |
| 3 | Hospital Aleman ( Site 0102) | Ciudad Autonoma de Buenos Aires | Buenos Aires | Argentina | C1118AAT |
| 4 | Centro de Educación Médica e Investigaciones Clínicas (CEMIC) ( Site 0103) | Buenos Aires | Argentina | 1431 | |
| 5 | FUNDALEU ( Site 0104) | Caba | Argentina | C1114AAN | |
| 6 | Box Hill Hospital ( Site 0203) | Box Hill | Victoria | Australia | 3128 |
| 7 | Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0300) | Rio de Janeiro | Brazil | 20231-050 | |
| 8 | Hospital Paulistano - Amil Clinical Research ( Site 0311) | Sao Paulo | Brazil | 01321-001 | |
| 9 | Tom Baker Cancer Centre ( Site 0401) | Calgary | Alberta | Canada | T4N 4N2 |
| 10 | The Ottawa Hospital ( Site 0404) | Ottawa | Ontario | Canada | K1H 8L6 |
| 11 | Jewish General Hospital ( Site 0400) | Montreal | Quebec | Canada | H3T 1E2 |
| 12 | Institut Paoli-Calmettes ( Site 0803) | Marseille | Bouches-du-Rhone | France | 13009 |
| 13 | Centre Hospitalier Lyon-Sud ( Site 0804) | Pierre Benite | Rhone-Alpes | France | 69495 |
| 14 | Hopital Saint Louis ( Site 0805) | Paris | France | 75010 | |
| 15 | Ha Emek Medical Center ( Site 1305) | Afula | Israel | 1834111 | |
| 16 | Soroka Medical Center ( Site 1307) | Beer-Sheva | Israel | 8410101 | |
| 17 | Rambam Medical Center ( Site 1301) | Haifa | Israel | 3109601 | |
| 18 | Hadassah Ein Karem Jerusalem ( Site 1300) | Jerusalem | Israel | 9112001 | |
| 19 | Chaim Sheba Medical Center ( Site 1302) | Ramat Gan | Israel | 5262001 | |
| 20 | Sourasky Medical Center ( Site 1303) | Tel Aviv | Israel | 6423906 | |
| 21 | A.O. Universitaria Policlinico S. Orsola-Malpighi ( Site 1400) | Bologna | Italy | 40138 | |
| 22 | ASST Spedali Civili di Brescia ( Site 1408) | Brescia | Italy | 25123 | |
| 23 | IRCCS Ospedale San Raffaele ( Site 1402) | Milano | Italy | 20132 | |
| 24 | Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1403) | Napoli | Italy | 80131 | |
| 25 | Fondazione IRCCS Policlinico San Matteo ( Site 1407) | Pavia | Italy | 27100 | |
| 26 | IRCCS - Arcispedale Santa Maria Nuova ( Site 1405) | Reggio Emilia | Italy | 42123 | |
| 27 | Uniwersytecki Szpital Kliniczny-Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku ( Site | Wroclaw | Dolnoslaskie | Poland | 50-367 |
| 28 | Pratia MCM Krakow ( Site 1601) | Krakow | Malopolskie | Poland | 30-510 |
| 29 | Szpitale Pomorskie Sp. z o.o. ( Site 1600) | Gdynia | Pomorskie | Poland | 81-519 |
| 30 | Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 2000) | Hospitalet de Llobregat | Barcelona | Spain | 08908 |
| 31 | Hospital Universitari Vall d'Hebron ( Site 2001) | Barcelona | Spain | 08035 | |
| 32 | Hospital Universitario 12 de Octubre ( Site 2003) | Madrid | Spain | 28041 | |
| 33 | Hospital Universitario de Salamanca ( Site 2002) | Salamanca | Spain | 37007 | |
| 34 | Inselspital Bern ( Site 2303) | Bern | Berne | Switzerland | 3010 |
| 35 | Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 2302) | Bellinzona | Ticino | Switzerland | 6500 |
| 36 | Ankara Universitesi Tip Fakultesi Cebeci Hastanesi ( Site 2400) | Ankara | Turkey | 06590 | |
| 37 | VKV Amerikan Hastanesi ( Site 2403) | Istanbul | Turkey | 34365 | |
| 38 | Dokuz Eylül Üniversitesi-Hematology ( Site 2402) | Izmir | Turkey | 35340 | |
| 39 | Kyiv City Clinical Hospital 9 ( Site 2502) | Kyiv | Ukraine | 04112 | |
| 40 | Nottingham University Hospitals NHS Trust. City Hospital Campus ( Site 2601) | Nottingham | England | United Kingdom | ng5 1pb |
| 41 | GenesisCare - Windsor ( Site 2608) | Windsor | England | United Kingdom | SL4 3HD |
| 42 | The Royal Marsden NHS Foundation Trust. ( Site 2606) | London | Surrey | United Kingdom | SM3 5PT |
| 43 | The Christie NHS Foundation Trust ( Site 2602) | Manchester | United Kingdom | M20 4BX |
Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 1026-003
- MK-1026-003
- 2020-002324-36