MODULATION OF VINBLASTINE RESISTANCE WITH CYCLOSPORINE - A PHASE-I STUDY

Objective: Tumor cell resistance is a major cause of failure to cure a dvanced malignancies. Multidrug resistance is thought to be an importa nt mechanism of such resistance. Our aims were to identify doses of cy closporine that would achieve blood levels effective in modulating mul tidrug resistance to vinblastine and to evaluate the toxicities and ma ximum tolerated dose of cyclosporine when administered in conjunction with vinblastine. Methods: We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by conti nuous intravenous infusion over 120 hours and vinblastine was administ ered by continuous infusion from hour 12 to hour 108. Sixty-two patien ts entered the trial, of whom 60 were evaluable. Results: Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduce d to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxi city at higher cyclosporine doses. The maximum tolerated dose of cyclo sporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Signif icant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lo wer than this maximum tolerated dose and was not cyclosporine dose dep endent. Myelosuppression, neurotoxicity, and transient hyperbilirubine mia were observed and were cyclosporine dose dependent. Conclusions: C yclosporine by continuous infusion may be safely given in high doses c oncurrently with continuous-infusion vinblastine. Plasma levels of cyc losporine greater-than-or-equal-to 1 mumol/L can be sustained during v inblastine administration. No sustained effect on T-cell subsets was o bserved. Vinblastine toxicity is enhanced by cyclosporine in a dose-de pendent fashion and correlates with cyclosporine-induced hyperbilirubi nemia.