NCCTG Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in newly diagnosed glioblastoma multiforme patients

BackgroundThe mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising pre-clinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study.MethodsAll patients received weekly oral RAD001 in combination with standard chemo-radiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. DLTs were defined during RAD001 combination therapy with TMZ/RT.ResultsEighteen patients were enrolled with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels with 1 patient on each dose level experiencing a DLT: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction …