title: A phase I trial of PR-104, a nitrogen mustard prodrug activated by both hypoxia and aldo-keto reductase 1C3, in patients with solid tumors.
abstract: OBJECTIVE
  PR-104 is a "pre-prodrug" designed to be activated to a dinitrobenzamide nitrogen mustard cytotoxin by nitroreduction in hypoxic regions of tumors. This study was conducted to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetics (PK) of PR-104 in patients with advanced solid tumors.
  
  
  METHODS
  Patients with solid tumors refractory or not amenable to conventional treatment were evaluated in a dose-escalation trial of PR-104 administered as a 1-h intravenous (IV) infusion every 3 weeks. The plasma PK of PR-104 and its primary metabolite, PR-104A, were evaluated.
  
  
  RESULTS
  Twenty-seven patients received a median of two cycles of PR-104 in doses ranging from 135 to 1,400 mg/m(2). The MTD of PR-104 as a single-dose infusion every 3 weeks was established as 1,100 mg/m(2). One of six patients treated at 1,100 mg/m(2) experienced DLT of grade 3 fatigue. Above the MTD, the DLTs at 1,400 mg/m(2) were febrile neutropenia and infection with normal absolute neutrophil count. No objective responses were observed, although reductions in tumor size were observed in patients treated at doses > or = 550 mg/m(2). The plasma PK of PR-104 demonstrated rapid conversion to PR-104A, with approximately dose-linear PK of both species.
  
  
  CONCLUSIONS
  PR-104 was well tolerated at a dose of 1,100 mg/m(2) administered as an IV infusion every 3 weeks. The area under the PR-104A plasma concentration-time curve at this dose exceeded that required for activity in human tumor cell cultures and xenograft models. The recommended dose of PR-104 as a single agent for phase II trials is 1,100 mg/m(2) and further trials are underway.
authors.affiliation: Regional Cancer Centre, Waikato Hospital, Private Bag 3200, Hamilton 3240, New Zealand. jameson@waikatodhb.govt.nz
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jameson
authors.forename: Danny
authors.initials: D
authors.lastname: Rischin
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.forename: John
authors.initials: J
authors.lastname: Gutheil
authors.forename: Adam V
authors.initials: AV
authors.lastname: Patterson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D019540:Area Under Curve; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D000860:Hypoxia; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D009097:Multienzyme Complexes; D009588:Nitrogen Mustard Compounds; C522381:PR-104; D011355:Prodrugs