title: A phase I clinical trial of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in patients with recurrent gynecologic cancer.
abstract: OBJECTIVE
  Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor (SSTR) that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the maximum tolerated dose (MTD), toxicities, clinical efficacy, and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer.
  
  
  METHODS
  Eligible patients were treated intraperitoneally for 3 days with 1 × 10(9) to 1 × 10(12) vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed using Common Toxicity Criteria (CTC) Adverse Events grading and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Imaging using In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding, and antibody response.
  
  
  RESULTS
  Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade I/II constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients showed stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies showed presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts.
  
  
  CONCLUSIONS
  This study shows the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted.
authors.affiliation: The Division of Gynecologic Oncology, Department of Radiology, The University of Alabama at Birmingham, Birmingham, Alabama 35249, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kim
authors.forename: Igor
authors.initials: I
authors.lastname: Dmitriev
authors.forename: Janis P
authors.initials: JP
authors.lastname: O'Malley
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Souheil
authors.initials: S
authors.lastname: Saddekni
authors.forename: Zhiying
authors.initials: Z
authors.lastname: You
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Preuss
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Harris
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Aurigemma
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
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*; D000368:Aged; D018394:CA-125 Antigen / Q000097:blood; D003131:Combined Modality Therapy; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000628:therapy*; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000628:therapy*; D017481:Receptors, Somatostatin / Q000235:genetics; D013004:Somatostatin / Q000096:biosynthesis; D014779:Virus Replication
chemical_list: D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins; D017481:Receptors, Somatostatin; D013004:Somatostatin; D015774:Ganciclovir