Phase I dose escalation study of sorafenib plus S-1 for advanced solid tumors

S-1, an oral pyrimidine fluoride-derived agent, is effective against various cancers. Sorafenib, an oral multikinase inhibitor, was found to prolong the survival of various cancers and enhance the cytotoxicity of chemotherapeutic agents. We conducted a phase I dose escalation study to determine dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors. Eligible patients received escalating doses (30, 35, and 40 mg/m(2) bid) of S-1 Day 1 (D1)-D14 and continuous sorafenib 400 mg bid from cycle 1 D8 every 21 days in a standard 3+3 study design. Primary endpoint was MTD. Thirteen patients were enrolled between May 2010 and Feb 2012. DLT developed in two (one grade 3 erythema and one prolonged grade 2 hand-foot-skin reaction) of the 6 patients at 35 mg/m(2) dose level. One pancreatic neuroendocrine tumor (pNET) patient achieved a durable partial response (27.9 months). Four colon cancer patients had stable disease and 3 of them had progression-free survival greater than 6 months. This study determined the recommended (MTD) S-1 dose of 30 mg/m(2) bid for this regimen. This result warrants further phase II studies for advanced pNET and colon cancer to evaluate the efficacy of this combination.

Automated summary

This study determined the maximal tolerated dose (MTD) of S-1 when combined with sorafenib for refractory solid tumors to be 30 mg/m(2) bid. Some patients achieved durable partial response or stable disease with this regimen. Further phase II studies are warranted to evaluate the efficacy of this combination in advanced pNET and colon cancer.