PHASE-II STUDY OF DEXVERAPAMIL PLUS ANTHRACYCLINE IN PATIENTS WITH METASTATIC BREAST-CANCER WHO HAVE PROGRESSED ON THE SAME ANTHRACYCLINE REGIMEN

The purpose of this study is to evaluate whether metastatic breast can cer that has progressed on an anthracycline-containing drug regimen wi ll subsequently respond to that identical regimen if dexverapamil, a m odulator of P-glycoprotein-mediated drug resistance, is given concomit antly, Eligible patients received 180 mg/m(2) dexverapamil every 6 h f or 15 doses with the anthracycline administered 30 min after the seven th dose. Blood for dexverapamil levels was drawn before and 30 min aft er this dose. When possible, biopsies were obtained to measure mdr-1 e xpression by reverse transcription-PCR and by image cytometry, Of the 21 patients entered onto the trial, 20 were evaluable for response. Th ere were two partial responses (10%) that both lasted for 6 months, an d two additional patients had stable disease. Seven patients had asymp tomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5 %), or prolongation of the P-R interval (14%), Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days af ter stopping it. Dexverapamil did not seem to increase anthracycline t oxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level w as 2164 ng/ml (range, 964-8382 ng/ml), There was poor correlation betw een reverse transcription-PCR and image cytometry for the level of mdr -1 expression. Because dexverapamil has been shown to affect doxorubic in pharmacokinetics subsequent to the initiation of this trial, it can not be concluded that the responses seen were necessarily due to P-gly coprotein inhibition, Additional studies are necessary to determine wh ether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.