title: Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response.
  
  
  RESULTS
  Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease.
  
  
  CONCLUSIONS
  Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.
authors.affiliation: Center for Gene and Cell Therapy, Okayama University Hospital, Okayama 700-8558, Japan. toshi_f@md.okayama-u.ac.jp
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanazawa
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohtani
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Saijo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sato
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
authors.forename: Sunil
authors.initials: S
authors.lastname: Chada
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Nakamura
authors.forename: Harubumi
authors.initials: H
authors.lastname: Kato
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged