title: A Phase I study of an intravesically administered immunotoxin targeting EpCAM for the treatment of nonmuscle-invasive bladder cancer in BCGrefractory and BCG-intolerant patients.
abstract: OBJECTIVE
  A Phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of the immunotoxin VB4-845 in patients with nonmuscle-invasive bladder cancer (NMIBC) refractory to or intolerant of bacillus Calmette-Guerin (BCG). Secondary objectives included evaluation of the safety, tolerability, pharmacokinetics, immunogenicity, and efficacy of VB4-845.
  
  
  METHODS
  Sixty-four patients with Grade 2 or 3, stage Ta or T1 transitional cell carcinoma or in situ carcinoma, either refractory to or intolerant of BCG therapy, were enrolled. Treatment was administered in ascending dose cohorts ranging from 0.1 to 30.16 mg. After receiving weekly instillations of VB4-845 to the bladder via catheter for 6 consecutive weeks, patients were followed for 4-6 weeks post-therapy and assessed at week 12.
  
  
  RESULTS
  An MTD was not determined, as a dose-limiting toxicity was not identified over the dose range tested. VB4-845 therapy was safe and well tolerated with most adverse events reported as mild; as a result, no patients were removed from the study in response to toxicity. By the end of the study, the majority of patients had developed antibodies to the exotoxin portion of VB4-845. A complete response was achieved in 39% of patients at the 12-week time point.
  
  
  CONCLUSIONS
  VB4-845 dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. Although an MTD was not determined at the doses administered, VB4-845 showed evidence of an antitumor effect that warrants further clinical investigation for the treatment of NMIBC in this patient population.
authors.affiliation: Viventia Biotechnologies Inc., Mississauga, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Kowalski
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Entwistle
authors.forename: Jeannick
authors.initials: J
authors.lastname: Cizeau
authors.forename: Demi
authors.initials: D
authors.lastname: Niforos
authors.forename: Shauna
authors.initials: S
authors.lastname: Loewen
authors.forename: Wendy
authors.initials: W
authors.lastname: Chapman
authors.forename: Glen C
authors.initials: GC
authors.lastname: MacDonald
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000009:adverse effects / Q000627:therapeutic use; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001500:BCG Vaccine; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D011993:Recombinant Fusion Proteins; C544997:VB4-845