Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: A neurofibromatosis clinical trials consortium phase II study

Abstract

Background: Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. Methods: We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. Results: The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI:14.3-23.7 mo), which was significantly longer than 11.9 months (P