4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide and Lymphoma--Non-Hodgkin

Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated.. In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules. The study enrolled 8 patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 13 with follicular lymphoma, 16 with diffuse large B-cell lymphoma (DLBCL), and 6 with mantle cell lymphoma. Correlation of tumor response with pharmacodynamic markers was determined in patients with meaningful clinical responses.. Cerdulatinib potently and selectively inhibited SYK/JAK signaling at tolerated exposures in patients with relapsed/refractory B-cell malignancies. The extent of target inhibition in whole-blood assays and suppression of inflammation correlated with tumor response. (ClinicalTrials.gov ID:NCT01994382).

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; B-Lymphocytes; Dose-Response Relationship, Drug; Female; Humans; Janus Kinases; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; Sulfones; Syk Kinase; Tumor Microenvironment