title: Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma.
  
  
  METHODS
  For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18-70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 × 10(12) viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28.
  
  
  RESULTS
  Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283-373) than in the control group (268 days, 210-313; hazard ratio [HR] 1·53, 95% CI 1·13-2·07; p=0·006). In a subgroup of patients with non-methylated MGMT, the HR was 1·72 (95% CI 1·15-2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369-574 for the experimental group vs 452 days, 95% CI 437-558 for the control group; HR 1·18, 95% CI 0·86-1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3-4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two).
  
  
  CONCLUSIONS
  Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy.
  
  
  BACKGROUND
  Ark Therapeutics Ltd.
authors.affiliation: University Hospital Eppendorf, Hamburg, Germany. westphal@uke.de
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Warnke
authors.forename: Philippe
authors.initials: P
authors.lastname: Menei
authors.forename: David
authors.initials: D
authors.lastname: Eckland
authors.forename: Judith
authors.initials: J
authors.lastname: Kinley
authors.forename: Richard
authors.initials: R
authors.lastname: Kay
authors.forename: Zvi
authors.initials: Z
authors.lastname: Ram
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005910:Glioma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D015996:Survival Rate; D013937:Thymidine Kinase / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; C529697:sitimagene ceradenovec; D015774:Ganciclovir