title: Using pharmacokinetic and pharmacodynamic data in early decision making regarding drug development: a phase I clinical trial evaluating tyrosine kinase inhibitor, AEE788.
abstract: OBJECTIVE
  In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients.
  
  
  METHODS
  Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues.
  
  
  RESULTS
  Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC(50)) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC(50) in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤ MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤ MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed.
  
  
  CONCLUSIONS
  Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. baselgaj@mskcc.org
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.forename: Frederico
authors.initials: F
authors.lastname: Rojo
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Clifford
authors.initials: C
authors.lastname: DiLea
authors.forename: William
authors.initials: W
authors.lastname: Mietlowski
authors.forename: Christie
authors.initials: C
authors.lastname: Low
authors.forename: Jerry
authors.initials: J
authors.lastname: Huang
authors.forename: Margaret
authors.initials: M
authors.lastname: Dugan
authors.forename: Kathryn
authors.initials: K
authors.lastname: Parker
authors.forename: Eric
authors.initials: E
authors.lastname: Walk
authors.forename: Allan
authors.initials: A
authors.lastname: van Oosterom
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D003657:Decision Making; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011687:Purines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D047428:Protein Kinase Inhibitors; D011687:Purines; C489254:AEE 788