title: Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors.
abstract: OBJECTIVE
  Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors.
  
  
  METHODS
  Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m(2). Pharmacokinetic assessments were performed during and after the first administration.
  
  
  RESULTS
  Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m(2) dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C (max) values of 103+/-17 ng/ml at the 13 mg/m(2) dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression > or =50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer.
  
  
  CONCLUSIONS
  The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m(2). The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m(2). The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.
authors.affiliation: Department of Medical Oncology, National Cancer Center Hospital, 104-0045 Tokyo, Japan. yayamada@ncc.go.jp
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kusaba
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Hideo
authors.initials: H
authors.lastname: Saka
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: J Patrick
authors.initials: JP
authors.lastname: McGovren
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Natsumeda
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C121395:edotecarin