CTEP has initiated about a dozen early phase trials testing various novel combinations of targeted agents for the treatment of three tumor types—glioma, melanoma, and renal cell cancer. The doublet combinations encompass a variety of strategies to intersect signaling via interruption of horizontal or vertical signaling pathways as well as incorporating antiangiogenesis therapies that have proven successful in the treatment of solid tumors. These studies will provide significant insights into the efficacy and potential toxicities of targeted agent combinations. As part of this initiative, a translational studies program is being implemented that will collect samples from patients entered in these trials. Promising preliminary results from the phase I studies of sorafenib plus bevacizumab and temsirolimus plus bevacizumab were reported at the 2007 annual meeting of the American Society of Clinical Oncology. Novel multi-arm phase II studies in renal cell cancer, glioblastoma, and melanoma are currently underway.