title: Phase I, pharmacokinetic, and pharmacodynamic study of intravenously administered Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene, in patients with advanced cancer.
abstract: OBJECTIVE
  The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity.
  
  
  METHODS
  Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues.
  
  
  RESULTS
  Seventeen patients received 36 courses of Ad5CMV-p53 at doses ranging from 3 x 10(10) to 3 x 10(12) virus particles (vp). Fatigue, nausea, vomiting, and fever were common, but rarely severe. Abnormalities of coagulation parameters, including decreases in fibrinogen and increases in fibrin degradation products at 3 x 10(12)vp, precluded additional dose escalation. Ad5CMV-p53 DNA could be detected in the plasma by polymerase chain reaction assay in the majority of patients at 14 days and 28 days at doses of 3 x 10(10) and higher. Six patients treated at 1 x 10(12)vp and 3 x 10(12)vp dose levels had Ad5CMV-p53 DNA detected within paired tumor tissue collected day 4.
  
  
  CONCLUSIONS
  Ad5CMV-p53 can be safely and repetitively administered up to 1 x 10(12)vp intravenously daily for 3 consecutive days. The absence of severe toxicities, the presence of circulating adenovirus 24 hours after administration, and detectable p53 transgene within tumor tissue distant from the site of administration demonstrates that systemic therapy with this adenoviral vector containing p53 is feasible.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA. atolcher@idd.org
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Desiree
authors.initials: D
authors.lastname: Hao
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Alex
authors.initials: A
authors.lastname: Miller
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond
authors.forename: Leslie
authors.initials: L
authors.lastname: Smetzer
authors.forename: Jill
authors.initials: J
authors.lastname: Van Wart Hood
authors.forename: James
authors.initials: J
authors.lastname: Merritt
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Dan
authors.initials: D
authors.lastname: Von Hoff
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D003587:Cytomegalovirus / Q000235:genetics*; D004247:DNA / Q000032:analysis / Q000097:blood; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000628:therapy*; D010314:Partial Thromboplastin Time; D011401:Promoter Regions, Genetic
chemical_list: D000914:Antibodies, Viral; D004247:DNA