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Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Purpose:
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.
Patients And 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.
Conclusion:
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.
Insights
Dexverapamil shows potential as a multidrug-resistance (MDR) reversal agent with reduced cardiac toxicity compared to verapamil. Further clinical trials are recommended for malignancies beyond renal cell carcinoma (RCC).
Area of Science:
- Pharmacology
- Oncology
- Cardiology
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer therapy.
- Verapamil, a calcium channel blocker, has shown potential in reversing MDR but suffers from cardiac toxicity.
- Dexverapamil, the dextro-(d-) stereoisomer of verapamil, exhibits reduced cardiac toxicity, making it a promising candidate for MDR reversal.
Purpose of the Study:
- To evaluate dexverapamil as a multidrug-resistance (MDR) reversal agent in patients with advanced renal cell carcinoma (RCC).
- To assess the safety and tolerability of dexverapamil when combined with vinblastine chemotherapy.
- To correlate plasma concentrations of dexverapamil with in vitro effects on vinblastine resistance.
Main Methods:
- Twenty-three patients with advanced RCC received vinblastine chemotherapy.
- Dexverapamil was administered orally every 6 hours for 12 doses, starting 18 hours before vinblastine.
- Two dosage groups were studied: 120 mg/m² (Group A) and 180 mg/m² plus dexamethasone (Group B).
Main Results:
- Toxicities observed included hypotension, asymptomatic bradycardia, and mild atrioventricular conduction delays.
- One patient experienced grade IV congestive heart failure, leading to dexverapamil discontinuation.
- Plasma concentrations of dexverapamil and norverapamil achieved were within the range shown to reverse vinblastine resistance in vitro.
Conclusions:
- Dexverapamil demonstrates potential as an MDR reversal agent with a favorable toxicity profile compared to racemic verapamil.
- The drug is suitable for further investigation in clinical trials for various malignancies exhibiting MDR.
- A feasible dosing schedule of 120 mg/m² orally every 6 hours, with dose escalation based on tolerance, is proposed for future studies.