Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.
OBJECTIVE
The reduced cardiac toxicity of the dextro-(d-) stereoisomer of verapamil (dexverapamil; Knoll Pharmaceuticals, Whippany, NJ) warrants its study as a potential multidrug-resistance (MDR) reversal agent.


METHODS
Twenty-three patients with advanced renal cell carcinoma (RCC) were treated with vinblastine at a dose of 0.11 mg/kg intravenous (IV) bolus injection on days 1 and 2 every 21 days. Dexverapamil was added to subsequent cycles after resistance had been demonstrated. Dexverapamil treatment was begun 18 hours before day 1 of vinblastine administration and was given orally every 6 hours for 12 doses. Patients in group A were treated with a dose of 120 mg/m2, and those in group B were treated with 180 mg/m2 plus dexamethasone; plasma concentrations achieved in patients were correlated with in vitro effects.


RESULTS
Toxicities included hypotension, asymptomatic bradycardia, and mild atrioventricular conduction delays, although one patient had dexverapamil discontinued for grade IV congestive heart failure. There were no partial or complete responses. The mean day-1 serum dexverapamil plus norverapamil plasma concentrations were 2,575 ng/mL (range, 697 to 6,015 ng/mL) for group A and 1,654 ng/mL (range, 710 to 4,132 ng/mL) for group B at the time of vinblastine administration. These concentrations were in the range of those that reversed vinblastine resistance in vitro.


CONCLUSIONS
The advantage of dexverapamil as an MDR reversal agent is its potential for achieving desired blood levels with substantially less toxicity than the racemic mixture of verapamil. Based on tolerability, it is a suitable drug for further study in clinical trials of malignancies other than RCC that attempt to achieve MDR reversal. The dose of 120 mg/m2 given orally every 6 hours, with dose escalation based on individual tolerance, represents a feasible schedule to be considered for such studies.
Motzer
R J
RJ
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Lyn
P
P
Fischer
P
P
Lianes
P
P
Ngo
R L
RL
Cordon-Cardo
C
C
O'Brien
J P
JP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D001919:Bradycardia / Q000139:chemically induced; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D014700:Verapamil / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*; D014747:Vinblastine / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014747:Vinblastine; C016904:norverapamil; D014700:Verapamil