title: Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.
abstract: OBJECTIVE
  To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.
  
  
  METHODS
  In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.
  
  
  RESULTS
  Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease > or =6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by >25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.
  
  
  CONCLUSIONS
  Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy.
authors.affiliation: Center for Sarcoma and Bone Oncology, Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Ming Hui
authors.initials: MH
authors.lastname: Chen
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Bello
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Darrel P
authors.initials: DP
authors.lastname: Cohen
authors.forename: Charles M
authors.initials: CM
authors.lastname: Baum
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019788:Fluorodeoxyglucose F18; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis* / Q000188:drug therapy* / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D017211:Treatment Failure
chemical_list: D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; D019788:Fluorodeoxyglucose F18; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib