title: Phase I dose-finding study of a new taxane, RPR 109881A, administered as a one-hour intravenous infusion days 1 and 8 to patients with advanced solid tumors.
abstract: OBJECTIVE
  To define the maximum-tolerated dose, recommended phase II dose (RD), dose-limiting toxicity (DLT), and pharmacokinetics of a novel taxane, RPR 109881A, administered on days 1 and 8 of a 21-day cycle.
  
  
  METHODS
  Twenty-nine patients were enrolled and treated according to a modified continual reassessment method from a starting dose of 7.5 mg/m(2) to 52.5 mg/m(2). Detailed pharmacokinetic analyses of blood and urine were performed on days 1 and 8 of the first cycle. Toxicity was monitored weekly.
  
  
  RESULTS
  DLT consisting of grade 3 or 4 diarrhea was seen in three of six patients at 52.5 mg/m(2). Grade 3 or 4 granulocytopenia was also seen in five of six patients treated at this dose (four of six in the first cycle). At the next lower dose level, 45 mg/m(2) toxicity was moderate, with only one of 12 patients experiencing severe diarrhea and grade 4 granulocytopenia with associated infection. Drug concentrations were consistent with a three-compartment open model. The total-body clearance suggests a linear dose-concentration relationship. RPR 109881A has a high clearance (mean, 42.6 L/h/m(2)), a large volume of distribution (mean, 952 L/m(2)), and a long terminal half-life (mean, 24 hours). There was no drug accumulation between days 1 and 8. One partial response was seen in a patient with renal cell carcinoma.
  
  
  CONCLUSIONS
  The RD of RPR 109881A given as a 1-hour infusion on days 1 and 8 of a 21-day cycle is 45 mg/m(2). At this dose the drug is well tolerated and should be further studied.
authors: British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, Canada. kgelmon@bccancer.bc.ca
authors: K A
authors: KA
authors: Gelmon
authors: J
authors: J
authors: Latreille
authors: A
authors: A
authors: Tolcher
authors: L
authors: L
authors: Génier
authors: B
authors: B
authors: Fisher
authors: D
authors: D
authors: Forand
authors: S
authors: S
authors: D'Aloisio
authors: L
authors: L
authors: Vernillet
authors: L
authors: L
authors: Daigneault
authors: A
authors: A
authors: Lebecq
authors: M
authors: M
authors: Besenval
authors: E
authors: E
authors: Eisenhauer
mesh_terms: D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects* / Q000031:analogs & derivatives*; D043823:Taxoids
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C413122:RPR 109881A; D043823:Taxoids; D017239:Paclitaxel