title: The raltitrexed-vinorelbine combination: a phase I pharmacokinetic and pharmacodynamic trial in advanced breast cancer.
abstract: OBJECTIVE
  Combinations of vinorelbine (VRB) and drugs targeting thymidylate synthase (TS) such as 5-fluorouracil (5-FU) have proven clinical efficacy in the management of advanced breast cancer. Raltitrexed (RTX) is a recent TS inhibitor which shows advantages over 5-FU in terms of a lower incidence of toxicity along with a simpler administration schedule. We conducted a phase I trial of the VRB-RTX combination in 12 patients with advanced breast cancer.
  
  
  METHODS
  Most of the patients were refractory to taxane-anthracycline combination therapy. Their median age was 51 years (range 33-70 years). RTX was given on day 1 and VRB on days 1 and 5 on a 3-week cycle. Three dose levels were initially planned with VRB and RTX increasing from 22.5 to 25 mg/m(2) and from 2.5 to 3 mg/m(2), respectively.
  
  
  RESULTS
  From a total of 50 cycles (mean 4 cycles per patient, range 1-11), the maximal tolerated dose (MTD) was reached at VRB 25 mg/m(2) and RTX 3 mg/m(2) with grade 3-4 neutropenia as the dose-limiting toxicity (7/16 cycles and 3/5 patients at the MTD). Nine pretreated patients were evaluable for treatment efficacy and three of these showed an objective response (one complete response, two partial responses; mean duration 26 weeks, range 17-38 weeks). Pharmacokinetic follow-up was done for both drugs (RTX by LC-MS-MS and VRB by HPLC-UV detection). There was no interaction between RTX and VRB pharmacokinetics since the VRB AUC was not significantly modified between day 1 and day 5. There was no relationship between RTX AUC and hematological toxicity. In contrast, there was a highly significant relationship between the mean VRB AUC (days 1-5) and the absolute neutrophil count decrease (Emax model, Hill constant=4.38+/-2.59, EC(50)=508+/-53.2 micro g.h/l, r=0.75, P=0.0013). A similar relationship was noted for the platelet decrease but at the limit of statistical significance.
  
  
  CONCLUSIONS
  The VRB-RTX combination appears to be a valuable treatment option in second-line treatment of advanced breast cancer. It is deliverable on an outpatient basis, shows an acceptable toxicity profile potentially manageable by VRB pharmacokinetic follow-up, and has promising antitumor activity in taxane-anthracycline-refractory patients. The recommended dose for further studies is VRB 22.5 mg/m(2) and RTX 3 mg/m(2).
authors.affiliation: Centre Antoine Lacassagne, Oncopharmacology Unit, Centre Antoine Lacassagne, 33, Avenue de Valombrose, 06189 Nice Cedex 2, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Ferrero
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.forename: Nicolas
authors.initials: N
authors.lastname: Magné
authors.forename: Frédéric
authors.initials: F
authors.lastname: Leccia
authors.forename: Rémy
authors.initials: R
authors.lastname: Largillier
authors.forename: Moïse
authors.initials: M
authors.lastname: Namer
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D012449:Safety; D016879:Salvage Therapy; D013876:Thiophenes / Q000008:administration & dosage; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077235:Vinorelbine
chemical_list: D011799:Quinazolines; D013876:Thiophenes; D014747:Vinblastine; C068874:raltitrexed; D000077235:Vinorelbine