In this Phase I trial, we explore the safety and tolerability of combining two epigenetic drugs: decitabine [a DNA methyltransferase (DNMT) inhibitor] and panobinostat [a histone deacetylase (HDAC) inhibitor], with traditional chemotherapy with temozolomide (an alkylating agent), setting the stage of epigenetic interruption of melanoma cell resistance. This evidence concerns the gene HDAC9 and melanoma.