title: First-in-human phase 0 trial of oral 5-iodo-2-pyrimidinone-2'-deoxyribose in patients with advanced malignancies.
abstract: OBJECTIVE
  Iododeoxyuridine (IdUrd), a halogenated nucleoside analog, produced clinical responses when administered as a radiosensitizer via continuous intravenous (c.i.v.) infusion over the course of radiotherapy. We conducted a phase 0 trial of 5-iodo-2-pyrimidinone-2'-deoxyribose (IPdR), an oral prodrug of IdUrd, in patients with advanced malignancies to assess whether the oral route was a feasible alternative to c.i.v. infusion before embarking on large-scale clinical trials. Plasma concentrations of IPdR, IdUrd, and other metabolites were measured after a single oral dose of IPdR.
  
  
  METHODS
  Eligible patients had advanced refractory malignancies. A single oral dose of IPdR was administered per patient and patients were followed for 14 days for safety assessments; dose escalations were planned (150, 300, 600, 1,200, and 2,400 mg) with one patient per dose level and 6 patients at the highest dose level. Blood sampling was conducted over a 24-hour period for pharmacokinetic analysis.
  
  
  RESULTS
  There were no drug-related adverse events. Plasma concentrations of IdUrd generally increased as the dose of IPdR escalated from 150 to 2,400 mg. All patients at the 2,400 mg dose achieved peak IdUrd levels of (mean ± SD) 4.0 μmol/L ± 1.02 μmol/L at 1.67 ± 1.21 hours after IPdR administration.
  
  
  CONCLUSIONS
  Adequate plasma levels of IdUrd were obtained to justify proceeding with a phase I trial of IPdR in combination with radiation. This trial shows the ability of a small, phase 0 study to provide critical information for decision-making regarding future development of a drug.
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA.
authors: Shivaani
authors: S
authors: Kummar
authors: Larry
authors: L
authors: Anderson
authors: Kimberly
authors: K
authors: Hill
authors: Eva
authors: E
authors: Majerova
authors: Deborah
authors: D
authors: Allen
authors: Yvonne
authors: Y
authors: Horneffer
authors: S Percy
authors: SP
authors: Ivy
authors: Larry
authors: L
authors: Rubinstein
authors: Pamela
authors: P
authors: Harris
authors: James H
authors: JH
authors: Doroshow
authors: Jerry M
authors: JM
authors: Collins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011741:Pyrimidine Nucleosides; C045889:ropidoxuridine
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