title: A phase I clinical trial of Ad5/3-Δ24, a novel serotype-chimeric, infectivity-enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer.
abstract: OBJECTIVE
  The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 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-Δ24 in recurrent ovarian cancer patients.
  
  
  METHODS
  Eligible patients were treated with IP Ad5/3-Δ24 for 3 consecutive days in one of three dose cohorts ranging 1 × 10(10)-1 × 10(12)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-Δ24 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-Δ24, as a potential therapeutic option for recurrent ovarian cancer patients.
authors.affiliation: The Division of Gynecologic Oncology, The University of North Carolina, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kim
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.forename: Souheil
authors.initials: S
authors.lastname: Saddekni
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kashentseva
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Harris
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Aurigemma
authors.forename: Sejong
authors.initials: S
authors.lastname: Bae
authors.forename: Karan P
authors.initials: KP
authors.lastname: Singh
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood*; D001201:Ascites / Q000821:virology; D018394:CA-125 Antigen / Q000097:blood; D023341:Chills / Q000821:virology; D018450:Disease Progression; D005221:Fatigue / Q000821:virology; D005260:Female; D005334:Fever / Q000821:virology; D015870:Gene Expression; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology; D010051:Ovarian Neoplasms / Q000097:blood / Q000628:therapy* / Q000821:virology; D014057:Tomography, X-Ray Computed; D014779:Virus Replication; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral; D018394:CA-125 Antigen
keywords: CRAd; Gene therapy; Infectivity-enhanced adenoviral vectors; Ovarian cancer