title: Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies.
abstract: OBJECTIVE
  ONYX-015 is a genetically modified adenovirus with a deletion of the E1B early gene and is therefore designed to replicate preferentially in p53-mutated cells. A Phase II trial of intralesional ONYX-015 was conducted in patients with hepatobiliary tumors to determine the safety and efficacy of such a treatment.
  
  
  METHODS
  All patients had biopsy-proven, measurable tumors of the liver, gall bladder, or bile ducts that were beyond the scope of surgical resection. Patients received intralesional injections of ONYX-015 at either 6 x 10(9) or 1 x 10(10) plaque-forming units/lesion up to a total dose of 3 x 10(10) plaque-forming units, and i.p. injections were allowed in patients with malignant ascites. The status of p53 was assessed by immunohistochemistry or Affymetrix GeneChip microarray analysis. Studies were conducted for viral shedding and for the presence of antiadenoviral antibodies before and after the injection of ONYX-015. Patients were assessed for response and toxicity.
  
  
  RESULTS
  Twenty patients were enrolled, and 19 patients were eligible. Half of the patients had primary bile duct carcinomas. Serious toxicities (> grade 2) were uncommon and included hepatic toxicity (three patients), anemia (one patient), infection (one patient), and cardiac toxicity (one patient, atrial fibrillation). Sixteen patients were evaluable for response. Among these evaluable patients, 1 of 16 (6.3%) had a partial response, 1 of 16 (6.3%) had prolonged disease stabilization (49 weeks), and 8 of 16 (50%) had a >50% reduction in tumor markers. Of the 19 eligible patients, 18 (94.7%) had specimens available for p53 analysis. Fifteen of these 18 patients (83.3%) had evidence of p53 mutation by one or both methods, although the methods correlated poorly. Viral shedding was confined to bile (two of two patients) and ascites (four of four patients). Pretreatment adenoviral antibodies were present in 14 of 14 patients and increased by 33.2% after ONYX-015 treatment.
  
  
  CONCLUSIONS
  Intralesional treatment with ONYX-015 in patients with hepatobiliary tumors is safe and well tolerated, and some patients had evidence of an anticancer effect. The high incidence of p53 mutations in these tumors makes this a logical population in which to test this therapy but precludes definitive evaluation about the necessity of a p53 mutation for ONYX-015 clinical activity.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Della
authors.initials: D
authors.lastname: Makower
authors.forename: Alla
authors.initials: A
authors.lastname: Rozenblit
authors.forename: Howard
authors.initials: H
authors.lastname: Kaufman
authors.forename: Morris
authors.initials: M
authors.lastname: Edelman
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Lane
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.forename: Hilda
authors.initials: H
authors.lastname: Haynes
authors.forename: Scott
authors.initials: S
authors.lastname: Wadler
mesh_terms: D000256:Adenoviridae / Q000254:growth & development / Q000276:immunology*; D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016158:Genes, p53; D006801:Humans; D015552:Injections, Intralesional; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016896:Treatment Outcome; D010948:Viral Plaque Assay; D014765:Viral Vaccines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D000914:Antibodies, Viral; D014765:Viral Vaccines; C464532:dl1520