What Is Nemtabrutinib?
Nemtabrutinib is an investigational drug currently being studied in clinical trials for various hematologic malignancies. It is administered orally. The drug is being explored for its potential to treat conditions such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and mantle cell lymphoma. Nemtabrutinib is not yet approved for any specific medical use. Its development involves extensive research to understand its effects, safety profile, and optimal use in patients. There are currently 21 clinical trials investigating nemtabrutinib, with a total enrollment of 3,453 participants. The first trial began in 2017, and the latest is projected to conclude in 2026.
Uses and Conditions Under Study
Nemtabrutinib is being investigated for several types of blood cancers and related conditions. The most frequently studied conditions include:
- Chronic Lymphocytic Leukemia (CLL): This is a slow-growing cancer that starts in white blood cells called lymphocytes. Nemtabrutinib is being studied in 6 trials for this condition.
- Small Lymphocytic Lymphoma (SLL): SLL is a slow-growing cancer that affects lymphocytes, similar to CLL but primarily found in the lymph nodes and spleen. Nemtabrutinib is being studied in 4 trials for SLL.
- Mantle Cell Lymphoma (MCL): This is a rare, aggressive type of non-Hodgkin lymphoma. Nemtabrutinib is being investigated in 3 trials for MCL.
- Marginal Zone Lymphoma (MZL): MZL is a slow-growing non-Hodgkin lymphoma that develops from B-lymphocytes. Nemtabrutinib is being studied in 2 trials for MZL.
- Follicular Lymphoma (FL): FL is a common, slow-growing type of non-Hodgkin lymphoma. Nemtabrutinib is being investigated in 2 trials for FL.
Other specific lymphomas under investigation include Gastric Mucosa-Associated Lymphoid Tissue Lymphoma, which is being studied in 1 trial. Broader categories such as Hematologic Malignancies, Hematological Malignancies, and Hematological Malignancy are also being explored in a total of 3 trials, encompassing a range of blood cancers.
In addition to studies in patients with these conditions, nemtabrutinib is also being studied in 6 trials involving healthy participants. These studies typically focus on understanding how the drug is absorbed, distributed, metabolized, and eliminated by the body, as well as its overall safety profile.
Dosing
Nemtabrutinib is administered orally, meaning it is taken by mouth. Clinical trials have explored different oral formulations, referred to as Nemtabrutinib Form A, Nemtabrutinib Form B, and Nemtabrutinib Form C. The drug is being studied both as a monotherapy (Nemtabrutinib alone) and in combination with other medications.
Combinations under investigation include nemtabrutinib with rituximab, pembrolizumab, lisocabtagene maraleucel, and venetoclax. Studies have also looked at potential drug interactions, such as when nemtabrutinib is taken with diltiazem, digoxin, itraconazole, or efavirenz. The development process includes Phase 1 dose escalation studies to determine the recommended Phase 2 dose (RP2D), followed by various expansion cohorts (e.g., Expansion Cohort A through Expansion Cohort I) to further evaluate the drug in specific patient populations, including those with relapsed or refractory lymphoma and leukemia. An Expansion Food Effect Cohort I has also been studied to understand how food might impact the drug's absorption.
Side Effects
A clinical study (NCT05673460) evaluated the safety of Nemtabrutinib in Japanese participants with hematological malignancies. This study reported the number of participants who experienced any adverse event (AE), but did not detail specific side effects or provide a comparison to a placebo group.
- Among participants receiving a 45 mg dose of Nemtabrutinib, 3 participants experienced adverse events.
- Among participants receiving a 65 mg dose of Nemtabrutinib, 4 participants experienced adverse events.
No participants in either dose group discontinued study treatment due to adverse events, and no dose-limiting toxicities were observed.
Clinical Trial Results
Clinical Study of Nemtabrutinib in Japanese Participants With Hematological Malignancies (NCT05673460)
This study investigated Nemtabrutinib in Japanese participants with hematological malignancies. It assessed how the drug behaved in the body (pharmacokinetics) and its initial effectiveness.
Pharmacokinetics
This part of the study measured how Nemtabrutinib was absorbed, distributed, metabolized, and excreted in the body.
- When participants received a 45 mg dose of Nemtabrutinib:
- The average total exposure to the drug over 24 hours (AUC0-24) was 8000 hr*ng/mL.
- The maximum concentration in the blood (Cmax) was 638 ng/mL.
- The drug reached its maximum concentration in the blood (Tmax) at a median of 1.88 hours.
- The minimum concentration in the blood (Cmin) was 190 ng/mL.
- When participants received a 65 mg dose of Nemtabrutinib:
- The average total exposure to the drug over 24 hours (AUC0-24) was 9890 hr*ng/mL.
- The maximum concentration in the blood (Cmax) was 917 ng/mL.
- The drug reached its maximum concentration in the blood (Tmax) at a median of 1.43 hours.
- The minimum concentration in the blood (Cmin) was 218 ng/mL.
These results indicate that higher doses led to higher drug exposure and concentration in the body.
Efficacy Results
The study also evaluated the objective response rate (ORR) as assessed by the investigator.
- For participants receiving 45 mg of Nemtabrutinib, the objective response rate was reported as both 0.0% and 100.0% in different participant groups or contexts within the study.
- For participants receiving 65 mg of Nemtabrutinib, the objective response rate was also reported as both 100.0% and 0.0% in different participant groups or contexts within the study.
The median duration of response (DOR) could not be determined for either the 45 mg or 65 mg dose, as it was reported as "NA" (Not Applicable/Available).
Currently Recruiting Trials
Nemtabrutinib is currently being investigated in several clinical trials for various hematologic malignancies and other conditions. These studies aim to evaluate its safety and effectiveness, sometimes alone and sometimes in combination with other treatments.
One ongoing Phase II trial, NCT06863402, is testing nemtabrutinib alongside pembrolizumab for patients with Richter transformation, diffuse large B-cell lymphoma subtype. This study, sponsored by Roswell Park Cancer Institute, plans to enroll up to 32 participants.
Another Phase II study, NCT07194980, from the Fred Hutchinson Cancer Center, is exploring nemtabrutinib combined with lisocabtagene maraleucel for relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This trial is designed for 20 participants.
For patients with mantle cell lymphoma, City of Hope Medical Center is sponsoring a Phase II trial, NCT06572618, which evaluates nemtabrutinib in combination with rituximab. This study aims to include 27 patients.
Merck Sharp & Dohme LLC is sponsoring a Phase I study, NCT06442436, focusing on the pharmacokinetics of nemtabrutinib in participants with moderate hepatic impairment compared to healthy individuals. This trial is enrolling 32 participants.
Two large Phase III trials are also underway for CLL/SLL. The NCT06136559 study, known as BELLWAVE-011, compares nemtabrutinib to investigator's choice of ibrutinib or acalabrutinib in first-line CLL/SLL, targeting 1200 participants. The BELLWAVE-010 study, NCT05947851, investigates nemtabrutinib plus venetoclax versus venetoclax plus rituximab in second-line or relapsed/refractory CLL/SLL, with an enrollment goal of 735 participants.
Finally, a broad Phase II study, NCT04728893, is assessing the efficacy and safety of nemtabrutinib in various hematologic malignancies, including CLL/SLL, Richter's transformation, marginal zone lymphoma, and mantle cell lymphoma. This trial has a target enrollment of 490 participants.
Where to Participate
Clinical trials for nemtabrutinib are being conducted across a wide geographic area, with studies active in 66 sites across 25 states and 55 cities. This broad reach helps ensure that patients in various regions have access to these research opportunities.
Some of the top locations with multiple active sites include:
- Spokane, Washington
- Madison, Wisconsin
- Denver, Colorado
- La Jolla, California
- Buffalo, New York
- Springdale, Arkansas
- Hackensack, New Jersey
- Waukee, Iowa
- San Antonio, Texas
- Torrance, California
Eligibility for these trials generally requires participants to be between 18 and 75 years of age, with studies open to all genders. While most trials focus on patients with specific conditions, some studies, such as those evaluating drug pharmacokinetics, may include healthy volunteers. Children are not eligible for participation in these nemtabrutinib trials.
Development Timeline
The journey of nemtabrutinib (also known as MK-1026) in clinical development began on May 22, 2017, with its first clinical trial. Initially, the research explored conditions like IBS-C and hyperphosphatemia, indicating an early broad investigation into its potential applications.
Over time, the focus of nemtabrutinib's development significantly shifted and expanded into the realm of hematologic malignancies. The pipeline grew to include a wide array of blood cancers, such as Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma, Marginal Zone Lymphoma, and Waldenstrom Macroglobulinemia, among others. This expansion reflects a growing understanding of nemtabrutinib's mechanism as a kinase inhibitor, specifically targeting the BTK protein, which is relevant in many B-cell cancers.
The primary sponsor driving much of this research has been Merck Sharp & Dohme LLC, which has sponsored 15 out of the 21 total trials. Other institutions like City of Hope Medical Center, Fred Hutchinson Cancer Center, and Roswell Park Cancer Institute have also contributed to its development.
To date, nemtabrutinib has been studied in a total of 21 clinical trials, enrolling 3,453 participants across various phases: 10 Phase I trials, 7 Phase II trials, and 3 Phase III trials, along with one Phase I/II study. The latest projected completion date for an ongoing trial is May 13, 2026, signaling continued active research and a commitment to advancing this potential treatment.