title: A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors.
abstract: OBJECTIVE
  This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme.
  
  
  METHODS
  Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m(2)/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m(2). Patients were eligible to continue on therapy until disease progression.
  
  
  RESULTS
  Thirty-one patients were enrolled and 28 were evaluable (range, 29-505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m(2)/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m(2) group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for >or =6 months, with the longest treatment duration of > or =16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses.
  
  
  CONCLUSIONS
  Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.
authors.affiliation: Taussig Cancer Center, Cleveland Clinic Foundation, OH 44195, USA. wengd@ccf.org
authors.forename: David E
authors.initials: DE
authors.lastname: Weng
authors.forename: Paul A
authors.initials: PA
authors.lastname: Masci
authors.forename: Susan F
authors.initials: SF
authors.lastname: Radka
authors.forename: T Elise
authors.initials: TE
authors.lastname: Jackson
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weiss
authors.forename: Ram
authors.initials: R
authors.lastname: Ganapathi
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Elson
authors.forename: William B
authors.initials: WB
authors.lastname: Capra
authors.forename: Vann P
authors.initials: VP
authors.lastname: Parker
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lockridge
authors.forename: J Wayne
authors.initials: JW
authors.lastname: Cowens
authors.forename: Nassim
authors.initials: N
authors.lastname: Usman
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Borden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016337:RNA, Catalytic / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D016337:RNA, Catalytic; D014841:von Willebrand Factor; D040281:Vascular Endothelial Growth Factor Receptor-1