title: Phase I and pharmacokinetic study of irofulven administered weekly or biweekly in advanced solid tumor patients.
abstract: OBJECTIVE
  We performed a Phase I and pharmacokinetic study to determine the maximum tolerated dose of irofulven (6-hydroxymethylacylfulvene; MGI-114, MGI PHARMA, Inc.), administered in intermittent weekly schedules in patients with advanced solid tumors.
  
  
  METHODS
  Three schedules were tested: A, days 1, 8, and 15 every 4 weeks; B, days 1 and 8 every 3 weeks; C, days 1 and 15 every 4 weeks. Drugs were administered as 5- and 30-min (schedules B and C) infusions. Dose levels of 10, 12, and 14 mg/m(2)/week were explored.
  
  
  RESULTS
  Ninety-nine patients received 256 cycles. Fifteen of 74 patients evaluable for maximum tolerated dose experienced 16 dose-limiting toxicities (5 of 17 patients on schedule A, 2 of 25 on schedule B, and 8 of 32 on schedule C), principally treatment delay for thrombocytopenia. Schedule A was considered unsuitable because of frequent thrombocytopenia and treatment discontinuations. Twenty-three percent of the overall population (22 patients with grade 1-2, and 1 patient with grade 3), including 37% of patients on dose level 3, experienced unexpected dose-limiting visual toxicity, which included color perception and visual field alterations linked to retinal cone cell toxicity; the visual toxicity had an early onset, was mostly reversible, and was related to higher dose per infusion. Safety profiles were similar for 5- and 30-min infusions. The relationships between dose and area under the plasma concentration-time curve and maximum plasma concentration were linear for both 5- and 30-min infusions in the 78 patients evaluated for pharmacokinetics. The area under the plasma concentration-time curve and clearance were comparable between infusion durations. Responses included one complete (ovarian), one partial (renal), and seven disease stabilizations lasting >4 months.
  
  
  CONCLUSIONS
  We recommend doses of 18 mg/m(2)/infusion for schedule B and 24 mg/m(2)/infusion for schedule C, limited to 0.55 mg/kg and a total dose of 50 mg/infusion, administered over 30-min.
authors.affiliation: Service de Médecine Interne 1, Hôpital Cochin, Paris, France. jerome.alexandre@cch.ap-hop-paris.fr
authors.forename: Jérôme
authors.initials: J
authors.lastname: Alexandre
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Mahmoud Ould
authors.initials: MO
authors.lastname: Kaci
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Brain
authors.forename: François
authors.initials: F
authors.lastname: Lokiec
authors.forename: Carmen
authors.initials: C
authors.lastname: Kahatt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Alejandro
authors.initials: A
authors.lastname: Yovine
authors.forename: François
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Smith
authors.forename: John R
authors.initials: JR
authors.lastname: MacDonald
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Misset
authors.forename: Esteban
authors.initials: E
authors.lastname: Cvitkovic
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D012717:Sesquiterpenes; C102714:irofulven