A PHASE I II TRIAL OF PACLITAXEL FOR NON-HODGKINS-LYMPHOMA FOLLOWED BY PACLITAXEL PLUS QUININE IN DRUG-RESISTANT DISEASE/

Patients with non-Hodgkin's lymphoma (NHL) recurrent after chemotherap y exhibit clinical characteristics compatible with the phenomenon of m ultidrug resistance (MDR) and frequently have detectable levels of P-g lycoprotein (P-gp). Paclitaxel has been used in recurrent NHL with lim ited success. To test whether clinical resistance to paclitaxel can be reversed, we treated patients having paclitaxel-resistant NHL with pa clitaxel plus quinine and measured the effects of quinine on paclitaxe l pharmacokinetics. Eligible patients had recurrent and measurable NHL . Patients initially received paclitaxel, 120 mg/m(2) (dose determined by a phase I trial of paclitaxel plus quinine), as a 20-24 h infusion every 3 weeks until there was evidence of clinical resistance. Patien ts then received paclitaxel at the same dose rate plus oral quinine at fixed dose rate of 400 mg three times each day. Paclitaxel pharmacoki netics were studied in each patient using paired samples from plasma o btained at the end of the 24 h paclitaxel infusion as an estimate of t he steady-state drug level. Of 14 patients treated with paclitaxel alo ne, one patient obtained a partial response (7%). At the time of disea se progession, one patient (same patient) obtained a partial response with paclitaxel plus quinine (7%). Steady-state paclitaxel levels were obtained in 12 patients. In 11 of 12 patients the steady-state paclit axel level was substantially lower with the addition of quinine. The a verage ratio of end of infusion plasma levels (paclitaxel alone/paclit axel plus quinine) was 0.6 (range 0.31-0.97) indicating a 40% decrease in paclitaxel levels with the addition of quinine ( p=0.001). We conc lude that paclitaxel given by this dose and schedule has modest activi ty in recurrent NHL. The addition of quinine to paclitaxel also have l imited activity, but the combination did reverse paclitaxel resistance in one patient, adding support to the hypothesis that clinical drug r esistance can be overcome with chemosensitizers in individual patients . Pharmacokinetic studies indicate that the reversal of drug resistanc e in this study cannot be attributed to changes in clearance of paclit axel (which appears to increase with quinine), but more likely to the sensitization of lymphoma cells. [(C) 1998 Rapid Science Ltd.].