Originally published as JCO Early Release 10.1200/JCO.2005.03.4116 on February 27 2006

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Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non–Small-Cell Lung Cancer

Toshiyoshi Fujiwara, Noriaki Tanaka, Susumu Kanazawa, Shoichiro Ohtani, Yasuo Saijo, Toshihiro Nukiwa, Kunihiko Yoshimura, Tetsuo Sato, Yoshikatsu Eto, Sunil Chada, Haruhiko Nakamura, Harubumi Kato

From the Center for Gene and Cell Therapy, Okayama University Hospital; Departments of Surgery and Radiology, Okayama University Graduate School of Medicine and Dentistry, Okayama; Department of Molecular Medicine, Tohoku University Graduate School of Medicine; Department of Respiratory Oncology and Molecular Medicine, Institute of Developing, Aging, and Cancer, Tohoku University, Sendai; Department of Gene Therapy, Institute of DNA Medicine, Department of Respiratory Medicine, Jikei University School of Medicine; Department of Surgery, Tokyo Medical University, Toyko, Japan; and Introgen Therapeutics Inc, Houston, TX

Address reprint requests to Toshiyoshi Fujiwara, MD, Center for Gene and Cell Therapy, Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan; e-mail: toshi_f{at}md.okayama-u.ac.jp

PURPOSE: 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).

PATIENTS AND 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 10⁹ to 1 x 10¹¹ 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.

CONCLUSION: 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.

Supported by grants from the Ministry of Education, Science, and Culture, Japan; and by grants from the Ministry of Health, Labour, and Welfare, Japan.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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