title: Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma.
abstract: OBJECTIVE
  MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site.
  
  
  METHODS
  MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies.
  
  
  RESULTS
  Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient).
  
  
  CONCLUSIONS
  MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.
authors.affiliation: Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: Andrew
authors.initials: A
authors.lastname: Slade
authors.forename: Gael
authors.initials: G
authors.lastname: Deplanque
authors.forename: Richard
authors.initials: R
authors.lastname: Harrop
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
authors.forename: Martin D
authors.initials: MD
authors.lastname: Forster
authors.forename: Rachel
authors.initials: R
authors.lastname: Gibson
authors.forename: Andreas
authors.initials: A
authors.lastname: Makris
authors.forename: Denis C
authors.initials: DC
authors.lastname: Talbot
authors.forename: Jan
authors.initials: J
authors.lastname: Steiner
authors.forename: Linda
authors.initials: L
authors.lastname: White
authors.forename: On
authors.initials: O
authors.lastname: Kan
authors.forename: Stuart
authors.initials: S
authors.lastname: Naylor
authors.forename: Miles W
authors.initials: MW
authors.lastname: Carroll
authors.forename: Sue M
authors.initials: SM
authors.lastname: Kingsman
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002272:Carcinoembryonic Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D065702:Cytochrome P-450 CYP2B6; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D018396:Mucin-1 / Q000032:analysis; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002272:Carcinoembryonic Antigen; D018396:Mucin-1; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating