Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jul 2006
Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 administered as a weekly 24 h continuous intravenous infusion in patients with advanced solid tumors.
BMS-214662 is a novel farnesyltransferase (FT) inhibitor that has shown promising suggestions of single agent activity in patients with advanced solid tumors when administered as a 1 h intravenous (i.v.) infusion every 3 weeks. The degree of FT inhibition in peripheral blood mononuclear cells (PBMCs) was greatest at the end of the infusion and rapidly reversed as the concentration of the drug in the plasma decayed. A second phase I trial of BMS-214662 administered as a weekly 24 h i.v. infusion was initiated to determine if the duration of maximum FT inhibition could be significantly extended by prolonging the infusion time and increasing the frequency of administration. ⋯ Administering BMS-214662 as a weekly 24 h continuous i.v. infusion permitted a considerably greater dose intensity to be delivered as compared to a single 1 h infusion given once every 3 weeks. The more prolonged infusion schedule resulted in a much lower degree of maximum FT inhibition in PBMCs than achieved with the 1 h infusion, although the duration of enzyme inhibition was longer, consistent with the lower peak plasma concentration of the drug provided by comparably tolerated doses when given as a 24 h infusion. Similarly, delivering the drug with increased dose intensity permitted by this weekly administration schedule did not appear to enhance its therapeutic benefit, at least in this phase I trial. Continued development of BMS-214662 may depend upon the potential for using it in combination with other anticancer drugs.