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Phase 0 trial investigating the intratumoural concentration and activity of sorafenib in neurofibromatosis type 2
  1. Sylwia Ammoun1,
  2. D Gareth Evans2,
  3. David A Hilton3,
  4. Adam Streeter4,
  5. Christopher Hayward5,
  6. C Oliver Hanemann1
  1. 1 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
  2. 2 Regional Genetic Service, St Mary's Hospital, Manchester, UK
  3. 3 University Hospitals Plymouth NHS Trust, Plymouth, UK
  4. 4 Medical Statistics, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
  5. 5 Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
  1. Correspondence to Professor C Oliver Hanemann, Peninsula Clinical Trials Unit, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth PL6 8BU, UK; Oliver.Hanemann{at}

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Schwannomas, meningiomas and ependymomas are tumours of the nervous system which occur sporadically or as part of the hereditary disease neurofibromatosis type 2 (NF2). Mutations in neurofibromin 2/NF2 gene cause all NF2-related schwannomas, meningiomas and ependymomas, 77% sporadic schwannomas, 60% sporadic meningiomas and 30% sporadic ependymomas.1 Schwannomas are the hallmark of NF2 and develop in all patients with NF2. Current treatments for NF2-related tumours are surgery or radiosurgery. Radiation may induce additional mutations and formation of secondary tumours in NF2 whereas surgery has limited use in patients with high tumour load or tumours located at the sites where resection would cause neurological complications.2 Avastin is effective but only in a fraction of patients.2 Published consensus recommendations suggest that the development of effective therapies for NF2 is urgent, with great potential for clinical progress.2

Platelet-derived growth factor receptor β (PDGFRβ) is overexpressed and activated in human primary schwannoma cells leading to increased proliferation.3 Using orally available, Food and Drug Administration (FDA)-approved cRAF/VEGFR-2/PDGFRβ inhibitor, sorafenib, this was successfully inhibited in vitro.3

Here we report an open-label, phase 0, single-agent trial (EudraCT: 2011-001789-16, REC: 11/LO/0771) testing sorafenib in patients with NF2 with the aim to determine whether molecular target inhibition occurs with oral sorafenib in patients with NF2 and whether target inhibition in plasma with oral sorafenib in patients with NF2 can act as a biomarker.


Per protocol minimal recruitment target depending on the pharmacodynamic (PD) response rate was three patients (two out of three or three out of five with 60% PD response).4 Here, five adult patients with NF2 with peripheral schwannomas (PS), diagnosed according to National Institute of Health (NIH) Diagnostic Criteria for NF, were treated with sorafenib administered orally at maximum tolerated dose (MTD) of 400 mg, two times a day, for 10 …

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  • Contributors SA: western blots on PS and PBMS, data evaluation, writing the manuscript. GE: collaborator and principal investigator. DAH: IHC analysis of PS tissues. AS: statistics. CH: PenCTU Trial Coordinator. COH: chief investigator, design of the trial, data evaluation, cowriting the manuscript.

  • Funding The Brain Tumour Charity, Saddlers House, 100 Reading Road, Yateley, Hampshire, GU46 7RX, UK. DGE is supported by the all Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.