title: A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours.
  
  
  METHODS
  Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed.
  
  
  RESULTS
  Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d).
  
  
  CONCLUSIONS
  200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination.
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. iain.macpherson@glasgow.ac.uk
authors.forename: I R
authors.initials: IR
authors.lastname: Macpherson
authors.forename: S
authors.initials: S
authors.lastname: Poondru
authors.forename: G R
authors.initials: GR
authors.lastname: Simon
authors.forename: R
authors.initials: R
authors.lastname: Gedrich
authors.forename: K
authors.initials: K
authors.lastname: Brock
authors.forename: C A
authors.initials: CA
authors.lastname: Hopkins
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.forename: A
authors.initials: A
authors.lastname: Stephens
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011804:Quinolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013876:Thiophenes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: C505207:OSI 930; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D013876:Thiophenes; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors