The raltitrexed-vinorelbine combination: a phase I pharmacokinetic and pharmacodynamic trial in advanced breast cancer

Abstract

Purpose. 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.

Materials and 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/m² and from 2.5 to 3 mg/m², 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/m² and RTX 3 mg/m² 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, EC₅₀=508±53.2 µg·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/m² and RTX 3 mg/m².