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

Brian Weiss, Brigitte C. Widemann, Pamela Wolters, Eva Dombi, Alexander Vinks, Alan Cantor, John Perentesis, Elizabeth Schorry, Nicole Ullrich, David H. Gutmann, James Tonsgard, David Viskochil, Bruce Korf, Roger J. Packer, Michael J. Fisher

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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<.001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. Conclusions: This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients.

Original languageEnglish
Pages (from-to)596-603
Number of pages8
JournalNeuro-oncology
Volume17
Issue number4
DOIs
StatePublished - Oct 14 2014

Keywords

  • NF1
  • Neurofibromatosis
  • Plexiform neurofibroma
  • Rapamycin
  • Sirolimus
  • mTOR

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