title: Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.
abstract: OBJECTIVE
  We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors.
  
  
  METHODS
  This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study.
  
  
  RESULTS
  Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses.
  
  
  CONCLUSIONS
  The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors.
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom. edward.kim@carolinas.org.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Jones
authors.affiliation: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Pilar
authors.initials: P
authors.lastname: Nava-Parada
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Salma
authors.initials: S
authors.lastname: Alam
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stephens
authors.affiliation: Astellas Pharma Global Development, Northbrook, Illinois.
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.affiliation: Astellas Pharma Global Development, Northbrook, Illinois.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.affiliation: Astellas Pharma Global Development, Northbrook, Illinois.
authors.forename: Rich
authors.initials: R
authors.lastname: Gedrich
authors.affiliation: UC San Diego Moores Cancer Center, San Diego, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Kaye
authors.affiliation: Drug Development Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Carden
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; 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; D055815:Young Adult
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