M. Lehnert et al., PHASE-II TRIAL OF DEXVERAPAMIL AND EPIRUBICIN IN PATIENTS WITH NONRESPONSIVE METASTATIC BREAST-CANCER, British Journal of Cancer, 77(7), 1998, pp. 1155-1163
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.