PHASE-I CROSSOVER STUDY OF PACLITAXEL WITH R-VERAPAMIL IN PATIENTS WITH METASTATIC BREAST-CANCER

Purpose: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) and r-ve rapamil, the less cardiotoxic stereoisomer, in heavily pretreated pati ents with metastatic breast cancer. Patients and Methods: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated oral ly with r-verapamil every 4 hours starting 24 hours before the same-do se 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determine d, seven additional patients who held not been treated with either dru g were evaluated to determine whether the addition of r-verapamil alte red the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitax el and after becoming refractory to paclitaxel therapy. Results: The M TD of the combination was 225 mg/m(2) of r-verapamil every 4 hours wit h paclitaxel 200 mg/m(2) by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 25 0 mg/m(2) r-verapamil. Fourteen patients received 32 cycles of r-verap amil at the MTD as outpatient therapy without developing cardiac toxic ity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 mu mol/L (range, 4.1 to 12.7) and 3.2 mu mol/L (range, 1. 9 to 6.3), respectively, which are within the range necessary for in v itro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and biliru bin levels. Hematologic toxicity from combined paclitaxel and r-verapa mil was significantly worse compared with the previous cycle of paclit axel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. Conclusion: r-Verapamil at 225 mg/m(2) orally every 4 hours can be given safely with paclitaxel 260 mg/m(2) by 3-hour infusi on as outpatient therapy and is associated with serum levels considere d active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.