title: Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy.
  
  
  METHODS
  In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed.
  
  
  RESULTS
  Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related.
  
  
  CONCLUSIONS
  Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
authors.affiliation: Tumor Biology Center, MR Development and Application Center, Albert Ludwigs University, Freiburg, Germany. drevs@sanafontis.com
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: Patrizia
authors.initials: P
authors.lastname: Siegert
authors.forename: Michael
authors.initials: M
authors.lastname: Medinger
authors.forename: Klaus
authors.initials: K
authors.lastname: Mross
authors.forename: Ralph
authors.initials: R
authors.lastname: Strecker
authors.forename: Ute
authors.initials: U
authors.lastname: Zirrgiebel
authors.forename: Jan
authors.initials: J
authors.lastname: Harder
authors.forename: Hubert
authors.initials: H
authors.lastname: Blum
authors.forename: Jane
authors.initials: J
authors.lastname: Robertson
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Puchalski
authors.forename: Helen
authors.initials: H
authors.lastname: Young
authors.forename: Owain
authors.initials: O
authors.lastname: Saunders
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D016037:Single-Blind Method; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D007211:Indoles
chemical_list: D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles