Mark W Kieran1, Julia Chisholm1, Michela Casanova1, Alba A Brandes1, Isabelle Aerts1, Eric Bouffet1, Simon Bailey1, Sarah Leary1, Tobey J MacDonald1, Francoise Mechinaud1, Kenneth J Cohen1, Riccardo Riccardi1, Warren Mason1, Darren Hargrave1, Stacey Kalambakas, Priya Deshpande1, Feng Tai1, Eunju Hurh, Birgit Geoerger1. 1. Pediatric Neuro-Oncology, Dana-Farber Boston Children's Cancer Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA; The Royal Marsden Hospital, Sutton, Surrey, UK; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Medical Oncology, Azienda USL-IRCCS Institute of Neurological Science, Bologna, Italy; Institut Curie and University Paris Descartes, Paris, France; Division of Haematology/Oncology at The Hospital for Sick Children, Toronto, Ontario, Canada; Sir James Spence Institute of Child Health Royal Victoria Infirmary, Newcastle, UK; Seattle Children's Hospital, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA; The Royal Children's Hospital, Children's Cancer Center, Melbourne, Australia; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA; Catholic University of the Sacred Heart, Rome, Italy; Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Paediatric Oncology Unit, Great Ormond Street Hospital, London, UK; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; Gustave Roussy, Department of Pediatric and Adolescent Oncology, University Paris-Sud, Université Paris-Saclay, Villejuif, France.
Abstract
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.
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.
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