Background: Metastatic melanoma patients have a poor prognosis. Currently only immunotherapy has offered a limited survival benefit. More effective and less toxic treatments are needed. Docetaxel (Taxotere) has clinical activity in melanoma and may be more active when combined with vinorelbine (Navelbine). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy (E4697). We therefore carried out a Phase II study of these three agents in patients with stage IV melanoma. Methods: Patients had documented stage IV melanoma and may have had prior immuno- or chemotherapy. Previously treated and controlled brain metastases were allowed. The DVS regimen: Docetaxel (40 mg/m2 IV), Vinorelbine (30 mg/m2 IV) were administered every 14 days, followed by GM-CSF (sargramostim, 250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was one year overall survival (OS) rate. Secondary objectives were median overall survival, response rate (per RECIST criteria) and the toxicity profiles. Results: Fifty-two patients were enrolled. 80% had M1c stage disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who had received prior biochemotherapy. Toxicity of the DVS regimen was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response of 15%, and disease stabilization in another 37%. Six-month progression free survival was 37%, and median overall survival was 11.4 months. Comparison to historical controls was made from a model by Korn et al (J Clin Oncol 2008; 26:527-34) that determines predicted one year OS rates for metastatic melanoma patients in single-arm phase II trials. While a historical one year OS of 24.3% was calculated, the actual one year OS rate for the patients in this trial was 48.1% (p = 0.01). Conclusions: The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable one-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted.