Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies

作者：Greg Coffey, Jiajia Feng, Andreas Betz, Anjali Pandey, Matt Birrell, Janet M. Leeds, Kenneth Der, Sabah Kadri, Pin Lu, Jeremy P. Segal, Y. Lynn Wang, Glenn Michelson, John T. Curnutte, Pamela B. Conley · 发表于：Clinical Cancer Research · 年份：2018 · DOI：10.1158/1078-0432.ccr-18-1047 · 被引用次数：40 · 研究领域：Chronic Lymphocytic Leukemia Research、Multiple Myeloma Research and Treatments、Lymphoma Diagnosis and Treatment

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: values against B-cell antigen receptor (BCR), IL2, IL4, and IL6 signaling pathways were 0.27 to 1.11 μmol/L, depending on the phosphorylation event. Significant correlations were observed between SYK and JAK pathway inhibition and tumor response. Serum inflammation markers were reduced by cerdulatinib, and several significantly correlated with tumor response. Diminished expression of CD69 and CD86 (B-cell activation markers), CD5 (negative regulator of BCR signaling), and enhanced expression of CXCR4 were observed in 2 patients with CLL, consistent with BCR and IL4 suppression and loss of proliferative capacity. CONCLUSIONS: Cerdulatinib potently and selectively inhibite...