PHASE-II TRIAL OF DEXVERAPAMIL AND EPIRUBICIN IN PATIENTS WITH NONRESPONSIVE METASTATIC BREAST-CANCER

Agents capable of reversing P-glycoprotein-associated multidrug resist ance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental pot ency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on ep irubicin toxicity, activity and pharmacokinetics in patients with meta static breast cancer. A two-stage design was applied. Patients first r eceived epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated ev ery 21 days. Patients with refractory disease continued to receive epi rubicin at the same dose and schedule but supplemented with oral dexve rapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to t he dexverapamil/epirubicin cohort of patients. Thirty-nine patients we re entered on study, 25 proceeded to receive epirubicin plus dexverapa mil. Dexverapamil did not increase epirubicin toxicity. The dose inten sity of epirubicin was similar when used alone or with dexverapamil. I n nine intrapatient comparisons, the area under the plasma concentrati on-time curve (AUG) of epirubicin was significantly reduced by dexvera pamil (mean 2968 vs 1901 mu g ml(-1) h(-1), P = 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapam il were 1.2 and 1.5 mu M respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable fo r tumour response (17%, CI 5-39%, s.e.(p) 0.079). The remissions laste d 3, 8, 11 and 11+ months. These data suggest that the concept of enha ncing chemotherapy activity by adding chemosensitizers may function no t only in haematological malignancies but also in selected solid tumou rs. An increase in the AUC and toxicity of cytotoxic agents does not s eem to be a prerequisite for chemosensitizers to enhance anti-tumour a ctivity.