title: Phase I dose-escalating trial of Escherichia coli purine nucleoside phosphorylase and fludarabine gene therapy for advanced solid tumors.
abstract: BACKGROUND
  The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation.
  
  
  METHODS
  A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m(2)) and escalating virus in the fourth (10(11)-10(12) viral particles, VP).
  
  
  RESULTS
  All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dose-dependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy.
  
  
  CONCLUSIONS
  This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted.
  
  
  BACKGROUND
  NCT01310179.
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham elr@stanford.edu.
authors.forename: E L
authors.initials: EL
authors.lastname: Rosenthal
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham.
authors.forename: T K
authors.initials: TK
authors.lastname: Chung
authors.affiliation: PNP Therapeutics, Inc., Birmingham.
authors.forename: W B
authors.initials: WB
authors.lastname: Parker
authors.affiliation: Southern Research Institute, Birmingham.
authors.forename: P W
authors.initials: PW
authors.lastname: Allan
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham.
authors.forename: L
authors.initials: L
authors.lastname: Clemons
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham.
authors.forename: D
authors.initials: D
authors.lastname: Lowman
authors.affiliation: Department of Cellular, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham.
authors.forename: J
authors.initials: J
authors.lastname: Hong
authors.affiliation: PNP Therapeutics, Inc., Birmingham.
authors.forename: F R
authors.initials: FR
authors.lastname: Hunt
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham.
authors.forename: J
authors.initials: J
authors.lastname: Richman
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham.
authors.forename: R M
authors.initials: RM
authors.lastname: Conry
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Vanderbilt University, Nashville, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mannion
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham.
authors.forename: W R
authors.initials: WR
authors.lastname: Carroll
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham.
authors.forename: L
authors.initials: L
authors.lastname: Nabell
authors.affiliation: PNP Therapeutics, Inc., Birmingham.
authors.forename: E J
authors.initials: EJ
authors.lastname: Sorscher
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000201:enzymology*; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D011683:Purine-Nucleoside Phosphorylase / Q000008:administration & dosage* / Q000235:genetics; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D011683:Purine-Nucleoside Phosphorylase; D014740:Vidarabine; C024352:fludarabine
keywords: fludarabine; gene therapy; human clinical trial; purine nucleoside phosphorylase