title: Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.
abstract: OBJECTIVE
  Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.
  
  
  METHODS
  Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.
  
  
  RESULTS
  Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher.
  
  
  CONCLUSIONS
  The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2).
authors.affiliation: Mount Vernon Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Patterson
authors.forename: Martin
authors.initials: M
authors.lastname: Zweifel
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Price
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Folkes
authors.forename: Michael R L
authors.initials: MR
authors.lastname: Stratford
authors.forename: Phil
authors.initials: P
authors.lastname: Ross
authors.forename: Sarah
authors.initials: S
authors.lastname: Halford
authors.forename: Jane
authors.initials: J
authors.lastname: Peters
authors.forename: Jai
authors.initials: J
authors.lastname: Balkissoon
authors.forename: Dai J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Anwar R
authors.initials: AR
authors.lastname: Padhani
authors.forename: Gordon J S
authors.initials: GJ
authors.lastname: Rustin
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011756:Diphosphates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes