Phase i study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

Mark W. Kieran, Julia Chisholm, Michela Casanova, Alba A. Brandes, Isabelle Aerts, Eric Bouffet, Simon Bailey, Sarah Leary, Tobey J. Macdonald, Francoise Mechinaud, Kenneth J. Cohen, Riccardo Riccardi, Warren Mason, Darren Hargrave, Stacey Kalambakas, Priya Deshpande, Feng Tai, Eunju Hurh, Birgit Geoerger

Research output: Contribution to journalArticlepeer-review


Background. Sonidegib (LDE225) is a potent, selective hedgehog (Hh) inhibitor of Smoothened. This study explored the safety and pharmacokinetics of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. Methods. Pediatric patients aged ?1 to <18 years were included according to a Bayesian design starting at 372 mg/ m2 of continuous once daily oral sonidegib. Tumor samples were analyzed for Hh pathway activation using a validated 5-gene Hh signature assay. In phase II, pediatric patients were treated at the recommended phase II dose (RP2D) while adults received 800 mg daily. Results. Sixteen adult (16 MB) and 60 pediatric (39 MB, 21 other) patients with an age range of 2-17 years were enrolled. The RP2D of sonidegib in pediatric patients was established at 680 mg/m2 once daily. The phase II study was closed prematurely.The 5-gene Hh signature assay showed that the 4 complete responders (2 pediatric and 2 adult) and 1 partial responder (adult) all had Hh-Activated tumors, while 5 patients with activated Hh had either stable disease (n = 3) or progressive disease (n = 2). No patient with an Hh-negative signature (n = 50) responded. The safety profile for pediatric patients was generally consistent with the one established for adult patients; however, growth plate changes were observed in prepubertal pediatric patients. Conclusions. Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.

Original languageEnglish (US)
Pages (from-to)1542-1552
Number of pages11
Issue number11
StatePublished - Nov 1 2017
Externally publishedYes


  • Clinical trial
  • Medulloblastoma
  • PTCH | SMO
  • Sonic hedgehog

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research


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