title: Phase I clinical and pharmacokinetic studies of the taxoid derivative RPR 109881A administered as a 1-hour or a 3-hour infusion in patients with advanced solid tumors.
abstract: OBJECTIVE
  To define the maximum tolerated dose (MTD), the recommended phase II dose, the optimal infusion duration and pharmacokinetics of the semisynthetic taxoid derivative RPR 109881A, given as a 1-h or 3-h infusion every 3 weeks.
  
  
  METHODS
  RPR109881A was administered as a 1-h i.v. infusion to 34 patients (study 1) with oral steroids as pre-medication. In a subsequent study, 29 patients were treated at the recommended dose or at the dose immediately below (study 2); the first 14 patients received RPR 109881A as a 3-h infusion, while the subsequent 15 were randomized to receive the drug as a 1-h or 3-h infusion. The pharmacokinetics of RPR109881A was studied in plasma and urine and for selected patients in some biological fluids (cerebrospinal fluid, pleural effusion, ascitis).
  
  
  RESULTS
  In study 1, the dose was escalated from 15 to 105 mg/m(2), at which dose two of five patients presented dose-limiting toxicities with febrile neutropenia (FN) after the first cycle, thus defining the MTD. The dose of 90 mg/m(2), at which grade 3/4 neutropenia was almost universal with FN in 18%, was recommended for phase II. At 90 mg/m(2) the incidence of diarrhea, fatigue and alopecia were 59, 29 and 70%, respectively. The results of study 2 were comparable to those of study 1, thus recommending the 1-h infusion duration for phase II evaluation. RPR 109881A exhibited a high total body clearance, a large distribution volume and long terminal half-life of 20 h. RPR 109881A was detected in cerebrospinal fluid shortly after the end of 1-h infusion. Three objective responses were observed in non-small-cell lung cancer (NSCLC) patients, including a patient with brain metastases.
  
  
  CONCLUSIONS
  The antitumor activity in NSCLC, the reproducible profile of toxicity and above all the ability to cross the blood-brain barrier make RPR 109881A worthy of further disease-oriented clinical development.
authors.affiliation: Oncology Institute of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona, Switzerland. csessa@ticino.com
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.forename: C
authors.initials: C
authors.lastname: Cuvier
authors.forename: S
authors.initials: S
authors.lastname: Caldiera
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: S
authors.initials: S
authors.lastname: Van Den Bosch
authors.forename: C
authors.initials: C
authors.lastname: Monnerat
authors.forename: D
authors.initials: D
authors.lastname: Semiond
authors.forename: D
authors.initials: D
authors.lastname: Pérard
authors.forename: A
authors.initials: A
authors.lastname: Lebecq
authors.forename: M
authors.initials: M
authors.lastname: Besenval
authors.forename: M
authors.initials: M
authors.lastname: Marty
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D001707:Biopsy, Needle; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D043823:Taxoids; D016896:Treatment Outcome
chemical_list: C413122:RPR 109881A; D043823:Taxoids; D017239:Paclitaxel