title: A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy.
  
  
  METHODS
  Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m(2) every 21 days (with an additional 1-2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response.
  
  
  RESULTS
  The most common non-hematologic toxicities were grade 1-2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1-2 thrombocytopenia and grade 3-4 neutropenia, leukopenia, and anemia. No grade 3-4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m(2) dose and one patient at the 13 mg/m(2) dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m(2). One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m(2). There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3-8% of the dose).
  
  
  CONCLUSIONS
  The recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.
authors.affiliation: Division of Hematology and Oncology, Duke University Medical Center, P.O. Box 3052, Durham, NC 27710, USA. hurwi004@mc.duke.edu
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: J Patrick
authors.initials: JP
authors.lastname: McGovren
authors.forename: Samit
authors.initials: S
authors.lastname: Hirawat
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Natsumeda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshinari
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001772:Blood Cell Count; D002227:Carbazoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005221:Fatigue / Q000139:chemically induced / Q000453:epidemiology; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000453:epidemiology; D006402:Hematologic Diseases / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000453:epidemiology; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology; D059004:Topoisomerase I Inhibitors; D014839:Vomiting / Q000139:chemically induced / Q000453:epidemiology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C121395:edotecarin