Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma
Mené sur 25 patients atteints d'un mélanome de stade avancé, cet essai de phase I évalue la toxicité et l'efficacité d'un traitement combinant sorafenib et temserolimus
Purpose: This phase I clinical trial was conducted to determine the safety, efficacy, and molecular effects of sorafenib with temsirolimus in patients with advanced melanoma. Experimental Design: Patients with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Sorafenib was given orally once or twice daily and temsirolimus was given intravenously weekly, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST criteria. Consenting patients with accessible tumors underwent optional tumor biopsies prior to treatment and after the second infusion of temsirolimus. Tumor biopsies were analyzed for activating mutations in BRAF and NRAS, and for expression of P-ERK and P-S6 proteins. Results: A total of 25 patients were accrued to the study. The MTD doses were sorafenib 400 mg qAM / 200 mg qPM daily and temsirolimus 25 mg IV weekly. Dose-limiting toxicities included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. There were no complete (CR) or partial (PR) responses with the combination; 10 patients achieved stabilization of disease as their best response. The median progression-free survival (PFS) was 2.1 months. Matching pre-treatment and day 15 tumor biopsies demonstrated marked inhibition of P-S6 with treatment in 3 of 4 evaluable patients, but minimal inhibition of P-ERK. Conclusions: Combination therapy with sorafenib and temsirolimus resulted in significant toxicity at higher dose levels, failed to achieve any clinical responses in genetically unselected patient population, and did not inhibit P-ERK.