Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellul ar accumulation of various anticancer drugs including anthracyclines and vi nca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitro and in an imal models. Here, we report an open phase I dose escalation trial in patie nts with refractory or relapsed malignant lymphoid diseases. Cinchonine dih ydrochloride was administered by continuous i.v. infusion for 48 h and esca lated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infus ion started 24 h before i.v. doxorubicin (25 mg/m(2)), vinblastine (6 mg/m( 2)), cyclophosphamide (600 mg/m(2)) and methyl-prednisolone (1 mg/kg/d) (CH VP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four pa tients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine adminis tered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolar ization was the main dose-limiting toxicity. No ventricular arrhythmia incl uding 'torsade de pointes' was observed. An MDR reversing activity was iden tified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influ ence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinc honine might be started 12 h before MDR-related chemotherapy infusion and r equires continuous cardiac monitoring but no reduction of cytotoxic drug do ses.