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-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. Patients and Methods: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who held not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. Results: The MTD of the combination was 225 mg/m(2) of r-verapamil every 4 hours with paclitaxel 200 mg/m(2) by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m(2) r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. 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 vitro 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 bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitaxel 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 infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.