A pilot study of sorafenib examining biomarkers in refractory or relapsed T-cell lymphoma patients.

Abstract

TPS300 Background: Aggressive T-cell lymphomas represent 10-15% of non-Hodgkin lymphomas and have a worse prognosis than aggressive B-cell lymphomas. The multikinase inhibitor sorafenib inhibits the Raf/Mek/Erk pathway, as well as the tyrosine kinases vascular endothelial growth factor receptors and platelet-derived growth factor receptor. Preclinical studies with sorafenib in B-cell lymphoma cell lines have demonstrated activity; however, the effect of sorafenib on T-cell lymphoma and leukemia cell lines has not been well established. We evaluated the inhibitory concentration (IC50) of sorafenib on Jurkat, HH and HUT78 cell lines. IC50 ranged from 1μ M to 15μ M while normal CD3+ cells remained insensitive to sorafenib at doses up to 15μ M. Based on these data a clinical trial of sorafenib for relapsed and refractory T-cell lymphoma patients has been initiated. Methods: This is a pilot study of sorafenib 400 mg orally twice daily in relapsed or refractory T- cell lymphomas including peripheral T-cell (PTCL), angioimmunoblastic T-cell (AITL), cutaneous T-cell (CTCL), anaplastic large cell (ALCL), and other transformed T-cell lymphomas. The primary objective is to study the biological effects of sorafenib on the MAPK pathway, specifically the inhibition of Erk phosphorylation, and to correlate with clinical activity in patients with T-cell lymphoma. We will examine changes in Erk phosphorylation of peripheral blood lymphocytes comparing day 29 levels to the baseline values. This will be done by a whole blood activation assay using phorbol myristate acetate (PMA). Erk phosphorylation will be assayed by flow cytometry (Chow et al, Cytometry 46:72–78, 2001). The secondary objective is to demonstrate the clinical activity by determining the response rate and progression-free survival. Exploratory objectives are to determine if there is an increased immunostimulatory TH1 response, and a decrease in the number of regulatory T-cells. Serial biopsies of cutaneous lesions will be analyzed for microvessel density. This trial is open with an accrual goal of 14 patients. If 3 or more patients respond out of 14 evaluable patients, this provides evidence of activity and the trial will be considered for further phase II study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx