Nemtabrutinib for Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) Refractory to Covalent Bruton Tyrosine Kinase Inhibitor or Pirtobrutinib and Previously Treated With a BCL2 Inhibitor

NCT07796373 | Not Yet Recruiting Phase 2 FDA Drug

• 2 other identifiers: 10002165002165-H
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) are diseases in which the body makes too many white blood cells that do not work properly. Because white cells play a role in immune function, people with CLL/SLL may be at greater risk of infections. CLL/SLL can be controlled with drugs, but many people develop resistance, and the treatments stop working. Objective: To test a new drug (nemtabrutinib) in people with CLL/SLL. Eligibility: People aged 18 years or older with CLL/SLL that persists despite treatment. Design: Participants will be screened. They will have imaging scans, blood and urine tests, and a test of their heart function. They will have a bone marrow biopsy: a sample of tissue and fluids will be drawn from inside their hip bone. They may also have a sample cut from a swollen lymph node, if one is safe to access. Nemtabrutinib is a tablet taken by mouth. Participants will take the drug once a day at home in 4-week cycles. They will have clinic visits at least every 4 weeks for the first 6 months and then every 3 months after that. Biopsies, imaging exams, and other tests may be repeated at these visits. Participants may also undergo lymphapheresis: Blood will be drawn from a tube inserted into a vein. The blood will pass through a machine that separates out cancer and immune cells. The remaining blood will be returned to the body through a different tube. Participants may stay in the study as long as the drug is helping them.

Conditions

Small Lymphocytic Leukemia; Chronic Lymphocytic Leukemia

Keywords

BTK Inhibitor; Pirtobrutinib; nemtabrutinib; BCL2 inhibitor; relapsed/refractory CLL

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR)

  ORR is defined as the proportion of subjects who achieve partial response (PR) or better, including partial response with lymphocytosis (PRL), as their best response. ORR will be evaluated separately in each cohort:CLL/SLL refractory to covalent BTK inhibitor (cBTKi) and previously treated with a BCL2 inhibitor and CLL/SLL refractory to pirtobrutinib and previously treated with a BCL2 inhibitor.

  After 6 cycles of nemtabrutinib

Secondary Outcomes (3)

• Progression-free survival (PFS) and time to response (TTR)

  PFS - time of disease progression or death from any cause; TTR - time to partial remission or better

• ORR, PFS, and TTR in BTK and PLCG2 wild-type and mutated CLL

  PFS - time to first sign of disease progression or death; TTR - time to partial remission or better; ORR - after 6 cycles with ongoing assessments.

• ORR, PFS, and TTR based on IGHV mutational status and cytogenetic abnormalities

  PFS - time to first sign of disease progression or death; TTR - time to partial remission or better; ORR - after 6 cycles with ongoing assessments.

Study Arms (1)

Treatment

EXPERIMENTAL

Nemtabrutinib 65 mg will be given orally once daily in 28-day cycles.

Drug: Nemtabrutinib

Interventions

Nemtabrutinib DRUG

Nemtabrutinib 65 mg will be given orally once daily in 28-day cycles and continue treatment until disease progression, unacceptable toxicity, or another discontinuation criterion is met.

Treatment

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Age \>=18 years. CLL/SLL is extremely rare in patients \< 18 years old.
• Ability to comprehend the investigational nature of the study and provide informed consent
• Confirmed diagnosis of CLL or SLL according to International Workshop on CLL (iwCLL) guidelines
• Coexpression of CD5, CD19, CD20, and CD23 expression and light-chain restriction
• CLL: clonal B-lymphocytosis \>=5,000 cells/mL OR SLL: lymphadenopathy with the tissue morphology of CLL but that are not leukemic, \<5,000 cells/mL
• Cohort A: refractoriness to cBTKi defined as lack of response or progressive disease while on therapy
• Cohort B: refractoriness to pirtobrutinib defined as lack of response or progressive disease while on therapy
• Prior treatment with a BCL2i
• Active disease requiring treatment or progressive disease during or after therapy according to iwCLL guidelines
• Measurable disease characterized by \>=1 of the following:
• Lymphadenopathy: \>=1 lymph node measuring \>=1.5 cm in the greatest diameter
• Splenomegaly: spleen measuring \>13 cm in craniocaudal length
• Lymphocytosis: \>=5,000 B cells/microL
• Bone marrow infiltration: CLL comprising \>=30% of all cells

You may not qualify if:

• The participant must be excluded from the study if the participant meets any of the following criteria:
• Documented CNS involvement
• Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
• Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
• Active, uncontrolled infection requiring systemic therapy, including IV antibiotics during screening. Participants may be rescreened followed completion of IV antibiotic course.
• Stroke or intracranial hemorrhage within 6 months of screening
• Hypertensive urgency or emergency
• Active, clinically significant cardiovascular disease including:
• Uncontrolled or symptomatic arrhythmias
• Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification
• Myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening.
• History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
• QTcF \>450 milliseconds based on Fridericia s formula (NOTE: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility).
• Known allergy/sensitivity to nemtabrutinib or any of the excipients (hypromellose acetate succinate, microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, and may include film coat).
• History of severe bleeding disorders defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Laura S Samples, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Laura S Samples, M.D.

CONTACT

(301) 827-1203; laura.samples@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2026
• First Posted: September 1, 2026
• Study Start (Estimated): October 7, 2026
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2031
• Last Updated: October 2, 2026

Record last verified: 2026-08-25

Locations

US (1)