title: Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.
abstract: OBJECTIVE
  To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.
  
  
  METHODS
  Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course.
  
  
  RESULTS
  Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses.
  
  
  CONCLUSIONS
  The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Mita
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Denis
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Johann S
authors.initials: JS
authors.lastname: Debono
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Goetz
authors.forename: Leonel
authors.initials: L
authors.lastname: Ochoa
authors.forename: Bahram
authors.initials: B
authors.lastname: Forouzesh
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Kathleen
authors.initials: K
authors.lastname: Molpus
authors.forename: Dorothée
authors.initials: D
authors.lastname: Semiond
authors.forename: Michèle
authors.initials: M
authors.lastname: Besenval
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; C532412:XRP6258