title: A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.
  
  
  METHODS
  Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.
  
  
  RESULTS
  The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.
  
  
  CONCLUSIONS
  Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression.
authors: Authors' Affiliations: Vall d'Hebron Institut d'Oncologia and Universitat Autonoma of Barcelona, Barcelona, Spain; University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; University of Leicester, Leicester, United Kingdom; University Hospital of Zürich, Zürich, Switzerland; Memorial Sloan-Kettering Cancer Center, New York, New York; Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors: Jordi
authors: J
authors: Rodon
authors: Hussein A
authors: HA
authors: Tawbi
authors: Anne L
authors: AL
authors: Thomas
authors: Ronald G
authors: RG
authors: Stoller
authors: Christian P
authors: CP
authors: Turtschi
authors: Jose
authors: J
authors: Baselga
authors: John
authors: J
authors: Sarantopoulos
authors: Devalingam
authors: D
authors: Mahalingam
authors: Yaping
authors: Y
authors: Shou
authors: Melissa A
authors: MA
authors: Moles
authors: Lin
authors: L
authors: Yang
authors: Camille
authors: C
authors: Granvil
authors: Eunju
authors: E
authors: Hurh
authors: Kristine L
authors: KL
authors: Rose
authors: Dereck D
authors: DD
authors: Amakye
authors: Reinhard
authors: R
authors: Dummer
authors: Alain C
authors: AC
authors: Mita
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000096:biosynthesis; D000071676:Zinc Finger Protein GLI1
chemical_list: D001713:Biphenyl Compounds; C400551:GLI1 protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C561435:sonidegib