title: A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.
abstract: OBJECTIVE
  We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer.
  
  
  METHODS
  A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 10(12), 3 × 10(12), 1 × 10(13) or 3 × 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status.
  
  
  RESULTS
  Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11).
  
  
  CONCLUSIONS
  Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.
authors.affiliation: Billings Clinic, Billings, Montana 59106, USA. Jburke@billingsclinic.org
authors.forename: James M
authors.initials: JM
authors.lastname: Burke
authors.forename: Donald L
authors.initials: DL
authors.lastname: Lamm
authors.forename: Maxwell V
authors.initials: MV
authors.lastname: Meng
authors.forename: John J
authors.initials: JJ
authors.lastname: Nemunaitis
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Stephenson
authors.forename: James C
authors.initials: JC
authors.lastname: Arseneau
authors.forename: Junko
authors.initials: J
authors.lastname: Aimi
authors.forename: Seth
authors.initials: S
authors.lastname: Lerner
authors.forename: Alex W
authors.initials: AW
authors.lastname: Yeung
authors.forename: Troy
authors.initials: T
authors.lastname: Kazarian
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Maslyar
authors.forename: James M
authors.initials: JM
authors.lastname: McKiernan
mesh_terms: D000260:Adenoviruses, Human; D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D003558:Cystoscopy / Q000379:methods; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D018579:Patient Selection; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology* / Q000652:urine
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor