title: Novel Phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416.
abstract: OBJECTIVE
  To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose.
  
  
  METHODS
  Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially.
  
  
  RESULTS
  Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of >35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels.
  
  
  CONCLUSIONS
  SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.
authors.affiliation: Developmental Therapeutics Program, Case Comprehensive Cancer Center, Department of Pathology and Radiology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. afsin.dowlati@CASE.edu
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Kelly
authors.initials: K
authors.lastname: Robertson
authors.forename: Tomas
authors.initials: T
authors.lastname: Radivoyevitch
authors.forename: John
authors.initials: J
authors.lastname: Waas
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Ziats
authors.forename: Paul
authors.initials: P
authors.lastname: Hartman
authors.forename: Fadi W
authors.initials: FW
authors.lastname: Abdul-Karim
authors.forename: Jay K
authors.initials: JK
authors.lastname: Wasman
authors.forename: Jack
authors.initials: J
authors.lastname: Jesberger
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lewin
authors.forename: Keith
authors.initials: K
authors.lastname: McCrae
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Scot C
authors.initials: SC
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001706:Biopsy; D015519:Bone Density; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules; D003287:Contrast Media / Q000494:pharmacology; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008833:Microcirculation; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010477:Perfusion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D015815:Cell Adhesion Molecules; D003287:Contrast Media; D019040:E-Selectin; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D018799:Intercellular Adhesion Molecule-1; C116890:Semaxinib