title: EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study.
abstract: BACKGROUND
  TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-α (TNF-α) under the control of the Egr-1 promoter, which is inducible by chemotherapy and radiation.
  
  
  OBJECTIVE
  This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC).
  
  
  METHODS
  TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m(2) daily over 5.5 weeks. Dose levels from 4 × 10(9) to 1 × 10(12) particle units (PU) were studied.
  
  
  METHODS
  Multicentered, academic institutions.
  
  
  METHODS
  Fifty patients with LAPC were treated.
  
  
  METHODS
  Doses of TNFerade Biologic were administered to patients.
  
  
  METHODS
  Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured.
  
  
  RESULTS
  Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 × 10(12) PU dose, making 4 × 10(11) PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months.
  
  
  CONCLUSIONS
  This is a Phase 1/2 non-randomized study.
  
  
  CONCLUSIONS
  Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 ×10(11) PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection.
authors.affiliation: Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.forename: James J
authors.initials: JJ
authors.lastname: Farrell
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosemurgy
authors.forename: Theodore
authors.initials: T
authors.lastname: Chung
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Chang
authors.forename: Milind
authors.initials: M
authors.lastname: Javle
authors.forename: Mitchell
authors.initials: M
authors.lastname: Posner
authors.forename: Irving
authors.initials: I
authors.lastname: Waxman
authors.forename: Anthony
authors.initials: A
authors.lastname: Reid
authors.forename: Richard
authors.initials: R
authors.lastname: Erickson
authors.forename: Marcia
authors.initials: M
authors.lastname: Canto
authors.forename: Amitabh
authors.initials: A
authors.lastname: Chak
authors.forename: Gretta
authors.initials: G
authors.lastname: Blatner
authors.forename: Milan
authors.initials: M
authors.lastname: Kovacevic
authors.forename: Mark
authors.initials: M
authors.lastname: Thornton
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002277:Carcinoma / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects; D002761:Cholangitis / Q000209:etiology; D004247:DNA / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D010195:Pancreatitis / Q000209:etiology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; C572333:TNFeraseBiologic; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D005472:Fluorouracil