Phase I Combination of Sorafenib and Erlotinib Therapy in Solid Tumors: Safety, Pharmacokinetic, and Pharmacodynamic Evaluation from an Expansion Cohort

摘要: The aims of this study were to further define the safety sorafenib and erlotinib, given at their full approved monotherapy doses, correlate pharmacokinetic pharmacodynamic markers with clinical outcome. In addition, a novel marker based on real-time measurement RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for 1-week run-in period, then both drugs together continuously. STC assessed in peripheral blood monocytes prior erlotinib initiation. Epidermal growth factor receptor (EGFR) expression K-RAS mutations measured archival tumor samples. Changes pERK CD31 determined fresh biopsies obtained pretreatment, dosing, during administration drugs. positron emission tomography-computed tomography scans assessments done. Eleven patients received total 57 cycles (median, 5; range, 1-10). Only four doses entire course, elevation liver enzymes being main reason dose reductions delays. Among 10 evaluable response, 8 experienced stabilization >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction sorafenib. Sorafenib-induced decrease RAF-STC showed statistically correlation time-to-progression seven patients. Other did not This drug combination resulted promising activity solid although toxicity warrants close monitoring. deserves as predictive