A phase I clinical trial of Ad5/3-¦¤24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer

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• 作者：Kenneth H. Kim ; Igor P. Dmitriev ; Souheil Saddekni ; Elena A. Kashentseva ; Raymond D. Harris ; Rosemarie Aurigemma ; Sejong Bae ; Karan P. Singh ; Gene P. Siegal ; David T. Curiel ; Ronald D. Alvarez
• 关键词：CRAd ; Gene therapy ; Infectivity-enhanced adenoviral vectors ; Ovarian cancer
• 刊名：Gynecologic Oncology
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：130
• 期：3
• 页码：518-524
• 全文大小：414 K

文摘

Objective

The conditionally replicative adenovirus Ad5/3-¦¤24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-¦¤24 achieves significant oncolysis and anti-tumor activity in ovarian cancer models. The purpose of this study was to evaluate in a phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-¦¤24 in recurrent ovarian cancer patients.

Methods

Eligible patients were treated with IP Ad5/3-¦¤24 for 3 consecutive days in one of three dose cohorts ranging 1 ¡Á 10¹⁰-1 ¡Á 10¹² vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response.

Results

Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grades 1-2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-¦¤24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect.

Conclusions

This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-¦¤24, as a potential therapeutic option for recurrent ovarian cancer patients.