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.
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
Documented CNS involvement
Active HBV/HCV infection. See Inclusion Criteria 10 (HBV) and 11 (HCV) for requirements.
Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible.
Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
Single group
Nemtabrutinib
DrugNemtabrutinib 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.
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.
Progression-free survival (PFS) and time to response (TTR)
Progression-free survival (PFS) and time to response (TTR) during treatment with nemtabrutinib 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
ORR, PFS, and TTR in BTK and PLCG2 wild-type and mutated CLL
PFS is measured from the first day of treatment until the first sign of disease progression or death from any cause. TTR is measured from the first day of treatment until the first occurrence of partial remission or better. Response-based endpoints (including ORR) are evaluated after 6 cycles for the primary response assessment, with ongoing assessments during treatment and follow-up as specified in the schedule of activities.
ORR, PFS, and TTR based on IGHV mutational status and cytogenetic abnormalities
PFS is measured from the first day of treatment until the first sign of disease progression or death from any cause. TTR is measured from the first day of treatment until the first occurrence of partial remission or better. Response-based endpoints (including ORR) are evaluated after 6 cycles for the primary response assessment, with ongoing assessments during treatment and follow-up as specified in the schedule of activities.
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