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@ARTICLE{Fangusaro:143857,
      author       = {J. Fangusaro and A. Onar-Thomas and T. Young Poussaint and
                      S. Wu and A. H. Ligon and N. Lindeman and A. Banerjee and R.
                      J. Packer and L. B. Kilburn and S. Goldman and I. F. Pollack
                      and I. Qaddoumi and R. I. Jakacki and P. G. Fisher and G.
                      Dhall and P. Baxter and S. G. Kreissman and C. F. Stewart
                      and D. T. W. Jones$^*$ and S. M. Pfister$^*$ and G. Vezina
                      and J. S. Stern and A. Panigrahy and Z. Patay and B. Tamrazi
                      and J. Y. Jones and S. S. Haque and D. S. Enterline and S.
                      Cha and M. J. Fisher and L. A. Doyle and M. Smith and I. J.
                      Dunkel and M. Fouladi},
      title        = {{S}elumetinib in paediatric patients with {BRAF}-aberrant
                      or neurofibromatosis type 1-associated recurrent,
                      refractory, or progressive low-grade glioma: a multicentre,
                      phase 2 trial.},
      journal      = {The lancet / Oncology Oncology},
      volume       = {20},
      number       = {7},
      issn         = {1470-2045},
      address      = {London},
      publisher    = {The Lancet Publ. Group},
      reportid     = {DKFZ-2019-01419},
      pages        = {1011-1022},
      year         = {2019},
      abstract     = {Paediatric low-grade glioma is the most common CNS tumour
                      of childhood. Although overall survival is good, disease
                      often recurs. No single universally accepted treatment
                      exists for these patients; however, standard cytotoxic
                      chemotherapies are generally used. We aimed to assess the
                      activity of selumetinib, a MEK1/2 inhibitor, in these
                      patients.The Pediatric Brain Tumor Consortium performed a
                      multicentre, phase 2 study in patients with paediatric
                      low-grade glioma in 11 hospitals in the USA. Patients aged
                      3-21 years with a Lansky or Karnofsky performance score
                      greater than 60 and the presence of recurrent, refractory,
                      or progressive paediatric low-grade glioma after at least
                      one standard therapy were eligible for inclusion. Patients
                      were assigned to six unique strata according to histology,
                      tumour location, NF1 status, and BRAF aberration status;
                      herein, we report the results of strata 1 and 3. Stratum 1
                      comprised patients with WHO grade I pilocytic astrocytoma
                      harbouring either one of the two most common BRAF
                      aberrations (KIAA1549-BRAF fusion or the BRAFV600E
                      [Val600Glu] mutation). Stratum 3 comprised patients with any
                      neurofibromatosis type 1 (NF1)-associated paediatric
                      low-grade glioma (WHO grades I and II). Selumetinib was
                      provided as capsules given orally at the recommended phase 2
                      dose of 25 mg/m2 twice daily in 28-day courses for up to 26
                      courses. The primary endpoint was the proportion of patients
                      with a stratum-specific objective response (partial response
                      or complete response), as assessed by the local site and
                      sustained for at least 8 weeks. All responses were reviewed
                      centrally. All eligible patients who initiated treatment
                      were evaluable for the activity and toxicity analyses.
                      Although the trial is ongoing in other strata, enrolment and
                      planned follow-up is complete for strata 1 and 3. This trial
                      is registered with ClinicalTrials.gov, number
                      NCT01089101.Between July 25, 2013, and June 12, 2015, 25
                      eligible and evaluable patients were accrued to stratum 1,
                      and between Aug 28, 2013, and June 25, 2015, 25 eligible and
                      evaluable patients were accrued to stratum 3. In stratum 1,
                      nine $(36\%$ $[95\%$ CI 18-57]) of 25 patients achieved a
                      sustained partial response. The median follow-up for the 11
                      patients who had not had a progression event by Aug 9, 2018,
                      was 36·40 months (IQR 21·72-45·59). In stratum 3, ten
                      $(40\%$ [21-61]) of 25 patients achieved a sustained partial
                      response; median follow-up was 48·60 months (IQR
                      39·14-51·31) for the 17 patients without a progression
                      event by Aug 9, 2018. The most frequent grade 3 or worse
                      adverse events were elevated creatine phosphokinase (five
                      $[10\%])$ and maculopapular rash (five $[10\%]).$ No
                      treatment-realted deaths were reported.Selumetinib is active
                      in recurrent, refractory, or progressive pilocytic
                      astrocytoma harbouring common BRAF aberrations and
                      NF1-associated paediatric low-grade glioma. These results
                      show that selumetinib could be an alternative to standard
                      chemotherapy for these subgroups of patients, and have
                      directly led to the development of two Children's Oncology
                      Group phase 3 studies comparing standard chemotherapy to
                      selumetinib in patients with newly diagnosed paediatric
                      low-grade glioma both with and without NF1.National Cancer
                      Institute Cancer Therapy Evaluation Program, the American
                      Lebanese Syrian Associated Charities, and AstraZeneca.},
      cin          = {B062 / B360},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)B360-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31151904},
      doi          = {10.1016/S1470-2045(19)30277-3},
      url          = {https://inrepo02.dkfz.de/record/143857},
}