J. Berlin et al., A PHASE-II STUDY OF VINBLASTINE IN COMBINATION WITH ACRIVASTINE IN PATIENTS WITH ADVANCED RENAL-CELL CARCINOMA, Investigational new drugs, 12(2), 1994, pp. 137-141
Renal cell carcinoma exhibits chemoresistance attributable in part to
the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic
antihistamine that has been shown in vitro to reverse this form of re
sistance. After five patients were treated on a dose-finding study, se
venteen patients with metastatic or unresectable renal cell carcinoma
were entered into a phase II study of vinblastine in combination with
acrivastine. Patients received oral acrivastine at doses of 400 mg eve
ry 4 hours for 6 days and a 96-hour continuous infusion of vinblastine
at a dose of 1.6 mg/m(2)/24 h. Of 15 evaluable patients, no tumor res
ponses were seen. The regimen was well-tolerated with the majority of
toxicities being gastrointestinal and hematologic. Serum levels of acr
ivastine, its principal metabolite (270C81) and vinblastine were measu
red during the study. Based on in vitro data, the plasma levels of acr
ivastine were within a range adequate to block P-glycoprotein activity
. High doses of acrivastine were well-tolerated clinically, however, t
he combination of acrivastine and vinblastine was not active against r
enal cell carcinoma.