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

Summary

Study Description: This is a phase 2 study of nemtabrutinib for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) refractory to treatment with covalent Bruton tyrosine kinase inhibitor (BTKi) or pirtobrutinib, and previously treated with B-cell lymphoma 2 inhibitor (BCL2i). Subjects will be treated with nemtabrutinib 65 mg by mouth once daily until disease progression or toxicity. Efficacy will be evaluated separately in CLL/SLL refractory to covalent BTKi (cBTKi) and in CLL/SLL refractory to pirtobrutinib. Efficacy will also be evaluated in molecular subgroups based on BTK and PLCG2 mutations, IGHV mutational status, and cytogenetic abnormalities. The pharmacodynamic effects of nemtabrutinib on tumor and immune cells will be assessed in peripheral blood, lymph node, and bone marrow. Clonal shifts during treatment with nemtabrutinib will be described. For the purposes of this protocol, the term CLL will be used throughout to refer collectively to chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), unless otherwise specified. Objectives: Primary Objectives: * Evaluate the efficacy of nemtabrutinib in CLL refractory to cBTKi and previously treated with BCL2i * Evaluate the efficacy of nemtabrutinib in CLL refractory to pirtobrutinib and previously treated with BCL2i Secondary Objectives: * Evaluate the efficacy of nemtabrutinib in CLL with and without BTK and PLCG2 mutations * Evaluate the efficacy of nemtabrutinib in CLL prognostic risk groups Exploratory Objectives: * Characterize the pharmacodynamic effects of nemtabrutinib on tumor and immune cells * Understand clonal shifts during treatment with nemtabrutinib * Identify potential biomarkers predictive of response to nemtabrutinib Endpoints: Primary Endpoints: * Overall response rate (ORR) to nemtabrutinib in CLL refractory to cBTKi and previously treated with BCL2i * ORR to nemtabrutinib in CLL refractory to pirtobrutinib and previously treated with BCL2i Secondary Endpoints: * Progression-free survival (PFS) and time to response (TTR) during treatment with nemtabrutinib in CLL refractory to cBTKi and previously treated with BCL2i * PFS and TTR during treatment with nemtabrutinib in CLL refractory to pirtobrutinib and previously treated with BCL2i * ORR, PFS, and TTR in BTK and PLCG2 wild-type and mutated CLL * ORR, PFS, and TTR based on IGHV mutational status and cytogenetic abnormalities Exploratory Endpoints: * Gene expression profiling in tumor and immune cells from peripheral blood, lymph node, and bone marrow during treatment with nemtabrutinib * Targeted or whole genome/exome sequencing of tumor cells during treatment with nemtabrutinib * Association between ORR, PFS, and potential biomarkers (e.g., molecular, serum) * Overall survival (OS) during treatment with nemtabrutinib in CLL refractory to cBTKi and previously treated with BCL2i * OS during treatment with nemtabrutinib in CLL refractory to pirtobrutinib and previously treated with BCL2i