ATNT-20A PHASE I-II TRIAL EVEROLIMUS AND SORAFENIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS: BRAIN TUMOR TREATMENT COLLABORATIVE TRIAL 09-01

BACKGROUND: Limited treatment options exist for patients with recurrent Malignant Gliomas (rMG), especially after Bevacizumab (BEV). Everolimus targets mTOR and sorafenib targets Raf, VEGF and PDFG. Combining these agents can block two parallel pathways simultaneously. We performed a phase I trial of Everolimus and Sorafenib in patients with rMG in preparation for a phase II study. METHODS: Patients with rMG u003e 18 yrs, KPS ≥ 60, normal laboratory data 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. The starting dose was Everolimus 5 mg a day + Sorafenib 400 mg twice a day with a dose de-escalation level of 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. 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 died due to disease progression with a median PFS of 4 weeks and OS of 20.9 weeks. CONCLUSION: This phase I study determined a phase II dose of 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 for Bev naive recurrent anaplastic gliomas and GBMs as well as recurrent GBM who failed BEV.