Nemtabrutinib

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).

The goal of this study is to evaluate nemtabrutinib compared with investigator's choice of ibrutinib or acalabrutinib in participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have not received any prior therapy. The primary hypotheses are that (1) nemtabrutinib is non-inferior to ibrutinib or acalabrutinib with respect to objective response rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria 2018 by blinded independent central review (BICR) and (2) nemtabrutinib is superior to ibrutinib or acalabrutinib with respect to progression free survival (PFS) per iwCLL Criteria 2018 by BICR.

This phase II trial tests how well nemtabrutinib and venetoclax work in treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cells (a type of white blood cell) in cancers such as CLL or SLL at abnormal levels. This may help keep cancer cells from growing and spreading. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Giving nemtabrutinib in combination with venetoclax may kill more cancer cells in patients with CLL or SLL.

This phase II trial tests the effect of nemtabrutinib in combination with rituximab in treating patients with marginal zone lymphoma. Nemtabrutinib, a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Giving nemtabrutinib in combination with rituximab may be safe, tolerable and/or effective in treating patients with marginal zone lymphoma.

This phase II trial tests the effect of nemtabrutinib in combination with brexucabtagene autoleucel (brexu-cel) in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Nemtabrutinib, a BTK inhibitor, may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chimeric antigen receptor (CAR) T-cell therapy, such as brexu-cel, is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Chemotherapy, such as fludarabine and cyclophosphamide, are given before CAR T cell therapy to help kill cancer cells in the body and help make room for the CAR T cells. Giving nemtabrutinib in combination with brexu-cel may be safe, tolerable, and/or effective in treating patients with relapsed or refractory mantle cell lymphoma.

The purpose of this study is to assess the safety and tolerability and to confirm the dose of nemtabrutinib in combination with venetoclax in participants with R/R CLL/SLL. The primary study hypotheses are that the combination of nemtabrutinib plus venetoclax is superior to VR with respect to progression-free survival (PFS) per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria as assessed by blinded independent central review (BICR).

This phase II trial tests how well nemtabrutinib in combination with pembrolizumab works in treating patients with Richter transformation, diffuse large B-cell lymphoma subtype (RT-DLBCL). Nemtabrutinib is in a class of medications called kinase inhibitors. It blocks a protein called BTK, which is present on B-cells (a type of white blood cell) in cancers such as Richter transformation at abnormal levels. This may help keep cancer cells from growing and spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Giving nemtabrutinib in combination with pembrolizumab may kill more cancer cells in patients with RT-DLBCL.

This phase II trial studies how well the addition of nemtabrutinib to lisocabtagene maraleucel in treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Nemtabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lisocabtagene maraleucel is a type of treatment called chimeric antigen receptor (CAR) T-cell therapy, in which a patient's T-cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T-cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T-cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T-cells are grown in the laboratory and given to the patient by infusion for treatment. Adding nemtabrutinib to lisocabtagene maraleucel may be an effective treatment for relapsed/refractory CLL/SLL.