title: Phase I trial of irofulven (MGI 114) in pediatric patients with solid tumors.
abstract: OBJECTIVE
  We performed a Phase I trial of irofulven (MGI 114) to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the plasma pharmacokinetics of irofulven in children < or=21 years of age with refractory/recurrent malignancies.
  
  
  METHODS
  Thirty-five patients were entered into the study, of whom 34 were eligible. Patients received Irofulven daily x 5 days every 28 days over 10 min, following pre-treatment with ondansetron (0.45 mg/kg) and dexamethasone (12 mg/m(2)). The initial dose of irofulven was 8 mg/m(2) daily, with subsequent escalations to 10, 13, and 17 mg/m(2). Plasma pharmacokinetic samples were obtained in a subset patients.
  
  
  RESULTS
  Thirty-two patients were assessable for toxicity, and 30 were assessable for response. In heavily pre-treated patients, dose-limiting thrombocytopenia was observed in two patients at the 8 mg/m(2)/day, and in one patient at the 6 mg/m(2)/day dose level. In less heavily pre-treated patients, proteinuria and elevated creatinine were dose limiting in two patients at the 17 mg/m(2)/day dose level. At 13 mg/m(2)/day, constipation, hyperkalemia with elevated creatinine, and thrombocytopenia was dose limiting in three patients. There were no complete or partial responses. One patient with poorly differentiated carcinoma had stable disease and received 11 courses of therapy. Patients demonstrated a lower systemic exposure and greater clearance than adults treated at similar dose levels.
  
  
  CONCLUSIONS
  The MTD of irofulven administered daily x 5 every 28 days with concomitant ondansetron and dexamethasone is 6 mg/m(2)/day in heavily pre-treated patients and 10 mg/m(2)/day in less heavily pre-treated patients.
authors.affiliation: Texas Children's Cancer Center/Baylor College of Medicine, Houston, Texas 77030, USA. lbomgaars@txccc.org
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Bomgaars
authors.forename: Gail C
authors.initials: GC
authors.lastname: Megason
authors.forename: Jeanette
authors.initials: J
authors.lastname: Pullen
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Langevin
authors.forename: Steve
authors.initials: S
authors.lastname: Dale Weitman
authors.forename: Linda
authors.initials: L
authors.lastname: Hershon
authors.forename: John G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: Mark
authors.initials: M
authors.lastname: Bernstein
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven