title: A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors.
abstract: OBJECTIVE
  OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors.
  
  
  METHODS
  This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules.
  
  
  RESULTS
  Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified.
  
  
  CONCLUSIONS
  At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors.
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee. igor.puzanov@vanderbilt.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Lindsay
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Laura
authors.initials: L
authors.lastname: Goff
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jeff
authors.initials: J
authors.lastname: Sosman
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois.
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.affiliation: OSI Pharmaceuticals, Boulder, Colorado.
authors.forename: Rich
authors.initials: R
authors.lastname: Gedrich
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stephens
authors.affiliation: Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. University of Glasgow, Glasgow, United Kingdom.
authors.forename: T R Jeffry
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines