title: Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors.
abstract: OBJECTIVE
  To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP).
  
  
  METHODS
  Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day -7 and day 22 of cycle 1.
  
  
  RESULTS
  Ninety-four patients (32F, 62M; ages, 39-87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (T(max) = 2-8 hours) and a terminal half-life (t(1/2)) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg.
  
  
  CONCLUSIONS
  IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.
authors.affiliation: University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado 80045, USA. antonio.jimeno@ucdenver.edu
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.forename: Bernard J C
authors.initials: BJ
authors.lastname: Eigl
authors.forename: Anne Lynne S
authors.initials: AL
authors.lastname: Chang
authors.forename: Joi
authors.initials: J
authors.lastname: Dunbar
authors.forename: Shannon
authors.initials: S
authors.lastname: Devens
authors.forename: Kerrie
authors.initials: K
authors.lastname: Faia
authors.forename: Georgios
authors.initials: G
authors.lastname: Skliris
authors.forename: Jeff
authors.initials: J
authors.lastname: Kutok
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.forename: William H
authors.initials: WH
authors.lastname: Sharfman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ross
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D000505:Alopecia / Q000139:chemically induced; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013035:Spasm / Q000139:chemically induced; D016896:Treatment Outcome; D014704:Veratrum Alkaloids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D053823:Hedgehog Proteins; C541444:IPI-926; D014704:Veratrum Alkaloids; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase