title: DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer.
abstract: OBJECTIVE
  H19 is a paternally imprinted oncofetal gene expressed in various embryonic tissues and in 85% of bladder tumors but suppressed in the adult healthy bladder. BC-819 is a DNA plasmid that carries the gene for diphtheria toxin-A under regulation of the H19 promoter sequence. We assessed the efficacy and toxicity of intravesical BC-819 instillations to prevent tumor recurrence and ablate a marker lesion in a phase 2b trial.
  
  
  METHODS
  A total of 47 patients with recurrent, multiple nonmuscle invasive bladder tumors in whom prior intravesical therapy had failed underwent transurethral resection of all except 1 marker tumor. Patients expressing H19 received a 6-week induction course of intravesical BC-819. Patients who achieved a complete response (absent new tumors at 3 months) were given 3 maintenance courses of 3-weekly instillations every 3 months.
  
  
  RESULTS
  All patients were evaluable for adverse effects and 39 were evaluable for efficacy. Complete tumor ablation was achieved in 33% of patients and in 64% there were no new tumors at 3 months. Median time to recurrence was 11.3 months in all cases but significantly longer (22.1 months) when analyzed by response status at 3 months. Adverse events were mild. The study was limited by the small number of patients.
  
  
  CONCLUSIONS
  BC-819 prevented new tumor growth in two-thirds of the patients and ablated a third of the marker lesions. Prolonged time to recurrence was observed in responding patients. These results along with the good safety profile make BC-819 a potential medication for bladder cancer.
authors.affiliation: Hadassah Ein-Kerem Medical Center, Jerusalem, Israel. Electronic address: ogofrit@gmail.com.
authors.forename: Ofer N
authors.initials: ON
authors.lastname: Gofrit
authors.affiliation: Edith Wolfson Medical Center, Sackler Faculty of Medicine, Holon, Israel.
authors.forename: Shalva
authors.initials: S
authors.lastname: Benjamin
authors.affiliation: Bnai-Zion Medical Center, Haifa, Israel.
authors.forename: Sarel
authors.initials: S
authors.lastname: Halachmi
authors.affiliation: Meir Medical Center, Kfar Saba, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Leibovitch
authors.affiliation: Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Dotan
authors.affiliation: University of Arizona, Phoenix, Arizona.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Lamm
authors.affiliation: Hillel Yafe Medical Center, Hadera, Israel.
authors.forename: Nahum
authors.initials: N
authors.lastname: Ehrlich
authors.affiliation: Hadassah Ein-Kerem Medical Center, Jerusalem, Israel.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yutkin
authors.affiliation: BioCancell Ltd., Jerusalem, Israel.
authors.forename: Monique
authors.initials: M
authors.lastname: Ben-Am
authors.affiliation: Hebrew University, Jerusalem, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Hochberg
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell; D004167:Diphtheria Toxin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage*; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D004167:Diphtheria Toxin; D010446:Peptide Fragments; C029795:diphtheria toxin fragment A
keywords: carcinoma; diphtheria toxin; plasmids; urinary bladder; urothelium