FINAL RESULTS OF A PROSPECTIVE MULTI-INSTITUTIONAL PHASE II STUDY OF EVEROLIMUS (RAD001), AN MTOR INHIBITOR, IN PEDIATRIC PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA. A POETIC CONSORTIUM TRIAL

Abstract

Purpose/Objective: The ras/raf signaling pathway is crucial in the development of pediatric low-grade gliomas. Aberrant ras/raf signaling is involved in tumorigenesis through promotion of cell proliferation, survival, and differentiation in sporadic LGG. Everolimus (RAD001) is a potent and selective inhibitor of mTOR, a downstream element of the ras/raf pathway. The activity, safety and pharmacokinetics of everolimus in pediatric patients with radiographic recurrent/progressive low-grade glioma are presented. Materials and Methods: Pediatric patients with radiographic progressive or recurrent lowgrade gliomas without neurofibromatosis type I were treated with oral everolimus 5mg/m2/ day once daily. Therapy was provided for 28 days (one cycle) and could be repeated for a total of 12 cycles. Response, as determined by standard 2-D MRI criteria was assessed for all patients. Pharmacogenetics, preliminary correlations of response with changes in pharmacodynamic parameters including p70s6 kinase activity as well as the toxicity profile and phamrmacokinetics of everolimus were also evaluated. Results: Twenty-three patients with a median age of 9 years (range, 3∗17 years) were enrolled, all of whom had received prior chemotherapy (average # regimens = 2.7) including progression after a carboplatin-containing regimen. Median number of cycles of therapy were 10 (range, 1-12). Responses were determined by blinded central review and included 4 patients with PR (>50% decrease) and 13 with stable disease (neither progressive disease (>25% increase) nor partial response (50% decrease). Six patients had progressive disease by one year. Overall therapy was well tolerated; two patients discontinued therapy due to mouth sores (n = 1) and withdrawal of consent (n = 1). PK parameters were similar to those previously reported in both adult and pediatric patients for this agent. Conclusions: Everolimus was well tolerated in pediatric patients with progressive or recurrent low-grade gliomas and demonstrated activity in this patient population. A similar trial of everolimus in NF1 associated low-grade gliomas is currently underway. Incorporation of everolimus into frontline LGG therapy is being proposed.