title: A phase I study with oral SU5416 in patients with advanced solid tumors: a drug inducing its clearance.
abstract: Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase inhibitor, and a potent inhibitor of VEGF-mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics of a Nanocrystal Colloidal Dispersion (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial; various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following i.v. administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME (Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should be applied in the development of next generation indoline anti-angiogenic and anti-tumor compounds.
authors.affiliation: University Hospital Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Salzberg
authors.forename: Miklos
authors.initials: M
authors.lastname: Pless
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
authors.forename: Klara
authors.initials: K
authors.lastname: Ambrus
authors.forename: Paul
authors.initials: P
authors.lastname: Scigalla
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib