Phase I/Ii Study Of The Combination Of Sorafenib And Temsirolimus In Patients With Metastatic Melanoma

9026 Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003. [Table: see text] No significant financial relationships to disclose.