Phase I dose-escalation study of sorafenib plus S-1 in refractory solid tumors

[[abstract]]Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (>6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers