title: Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.
abstract: OBJECTIVE
  The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed.
  
  
  METHODS
  Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed.
  
  
  RESULTS
  Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin.
  
  
  CONCLUSIONS
  GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted.
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan; Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Josina C
authors.initials: JC
authors.lastname: Reddy
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Walter C
authors.initials: WC
authors.lastname: Darbonne
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Kenn L
authors.initials: KL
authors.lastname: Zerivitz
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007010:Hyponatremia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D000071676:Zinc Finger Protein GLI1
chemical_list: D000813:Anilides; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1