Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer

A. W. Tolcher, K. H. Cowan, D. Solomon, F. Ognibene, B. Goldspiel, R. Chang, M. H. Noone, A. M. Denicoff, C. S. Barnes, M. R. Gossard, P. A. Fetsch, S. L. Berg, F. M. Balis, D. J. Venzon, J. A. O'Shaughnessy

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73 Scopus citations

Abstract

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 far a total of 12 doses. Once the maximum- tolerated dose (MTD) of the combination was determined, seven additional patients who had 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/m2 of r- verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose- limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 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 μmol/L (range, 4.1 to 12.7) and 3.2 μmol/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/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 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.

Original languageEnglish (US)
Pages (from-to)1173-1184
Number of pages12
JournalJournal of Clinical Oncology
Volume14
Issue number4
DOIs
StatePublished - Apr 1996
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Tolcher, A. W., Cowan, K. H., Solomon, D., Ognibene, F., Goldspiel, B., Chang, R., Noone, M. H., Denicoff, A. M., Barnes, C. S., Gossard, M. R., Fetsch, P. A., Berg, S. L., Balis, F. M., Venzon, D. J., & O'Shaughnessy, J. A. (1996). Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer. Journal of Clinical Oncology, 14(4), 1173-1184. https://doi.org/10.1200/JCO.1996.14.4.1173