Background: Limited treatment options exist for patients with recurrent Malignant Gliomas (MG), especially after failing Bevacizumab (BEV). Signal transduction pathways involved in gliomagenesis provide therapeutic targets. Everolimus targets mTOR which is an important node downstream from PI3K and Akt. Sorafenib targets Raf, as well as VEGF and PDFG. The rationale for combining these agents is to inhibit two parallel pathways simultaneously. We performed a phase I trial of Everolimus and Sorafenib in patients with recurrent malignant gliomas in preparation for a phase II study. Methods: Patients with recurrent MG > 18 yrs, KPS ≥ 60, adequate hematologic, renal and hepatic function and no history of HIV or hepatitis were eligible. No limit on prior relapses and BEV exposure was allowed. Enzyme inducing seizure drugs were not allowed. A 3 + 3 dose escalation was used to determine the MTD, defined as the highest dose combination resulting in 0/3 or 1/6 patients experiencing a DLT. The starting dose was Everolimus 5 mg a day + Sorafenib 400 mg twice a day with a plan to increase to a maximum dose of 10 mg a day and 800 mg twice a day over several defined dose levels. A de-escalation level was Everolimus 5 mg/day + Sorafenib 400 mg twice a day for 7 days on and 7 days off. Results: 11 men and 2 women were enrolled with a median age of 50 years (19-66) and median KPS of 80 (70-100). All patients had a GBM with 7 receiving prior BEV therapy. In cohort 1, 3 of 6 patients experienced a DLT which were grade 3: fatigue, chest pain, HTN, elevated ALT, hypercholesterolemia and hyperglycemia and one grade 4 hypertriglyceridemia. Dose de-escalation occurred with 1 of 7patients having a DLT of myositis, nausea, fatigue, hypertension and hypercholesterolemia-all grade 3. All patients have died due to disease progression with a median PFS of 4 weeks and OS of 20.9 weeks. Conclusions: This phase I study determined the phase II dose in patients with recurrent malignant glioma to be Everolimus at 5 mg daily and Sorafenib at 400 mg BID 7 days on and 7 days off. A phase II trial is on-going investigating this regimen in Bev naive recurrent anaplastic gliomas and GBMs as well as recurrent GBM who failed BEV. Clinical trial information: NCT01434602