title: Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer.
abstract: OBJECTIVE
  A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months.
  
  
  METHODS
  A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 10(9) to 3 × 10(11) particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months.
  
  
  RESULTS
  Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity was encountered. Urgency was the most common adverse event and all cases were grade 1 or 2. rAd-IFNα DNA was not detected in the blood. However, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses of 10(10) or more particles per ml with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months, respectively.
  
  
  CONCLUSIONS
  Intravesical rAd-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin.
authors.affiliation: Department of Urology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. cdinney@mdanderson.org
authors.forename: Colin P N
authors.initials: CP
authors.lastname: Dinney
authors.forename: Mark B
authors.initials: MB
authors.lastname: Fisher
authors.forename: Neema
authors.initials: N
authors.lastname: Navai
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Donnell
authors.forename: David
authors.initials: D
authors.lastname: Cutler
authors.forename: Alice
authors.initials: A
authors.lastname: Abraham
authors.forename: Sophia
authors.initials: S
authors.lastname: Young
authors.forename: Beth
authors.initials: B
authors.lastname: Hutchins
authors.forename: Maria
authors.initials: M
authors.lastname: Caceres
authors.forename: Narendra
authors.initials: N
authors.lastname: Kishnani
authors.forename: George
authors.initials: G
authors.lastname: Sode
authors.forename: Constance
authors.initials: C
authors.lastname: Cullen
authors.forename: Guangcheng
authors.initials: G
authors.lastname: Zhang
authors.forename: H Barton
authors.initials: HB
authors.lastname: Grossman
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.forename: Marshall
authors.initials: M
authors.lastname: Gonzales
authors.forename: Michael
authors.initials: M
authors.lastname: Kincaid
authors.forename: Nancy
authors.initials: N
authors.lastname: Ainslie
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Maneval
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Wszolek
authors.forename: William F
authors.initials: WF
authors.lastname: Benedict
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000008:administration & dosage; D002295:Carcinoma, Transitional Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002793:Cholic Acids / Q000008:administration & dosage; D004187:Disaccharides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D018570:Risk Assessment; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*
chemical_list: D001500:BCG Vaccine; D002793:Cholic Acids; D004187:Disaccharides; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; C525256:Syn3 compound
keywords: AE; AWD; BCG; CR; DLT; IFN; LLOQ; NED; NMIBC; adverse event; alive with disease; bacillus Calmette-Guérin; complete response; dose limiting toxicity; genetic therapy; interferon; interferons; lower limit of quantitation; no evidence of disease; nonmuscle invasive bladder cancer; urinary bladder neoplasms