EVALUATION OF THE COMBINATION OF VINBLASTINE AND QUINIDINE IN PATIENTS WITH METASTATIC RENAL-CELL CARCINOMA - A PHASE-I STUDY

Quinidine is known to inhibit p-glycoprotein and enhance the activity of vinblastine against cultured renal carcinoma cells. We have combined quinidine and vinblastine in a Phase I trial in patients with metastatic renal cell carcinoma. Twenty-three patients were entered. Prior treatment included nephrectomy (15 patients), radiation (1 patient) and interferons (8 patients), Cohorts of patients were treated at one of three quinidine dose levels (100, 200, and 400 mg); one patient received 300 mg. Quinidine was given orally 4 times daily starting 3 days prior to the first dose of vinblastine of 5 mg/m(2) intravenously given once a week. Hematologic parameters, EKG, and quinidine levels were monitored weekly. Mean quinidine levels in each dose tier were 1.58, 2.59, and 4.24 mu g/ml, respectively. The dose-limiting toxicity was leukopenia, which necessitated dose interruptions in 16 patients. The mean nadir WBC count (X10(9)/L) was 3.47, 2.3, and 1.73 in each dose tier, respectively. Corresponding values for the mean maximum decrease in WBC count from baseline were 3.85, 5.86, and 6.53, respectively. There was a trend for leukopenia to become more severe with increasing doses of quinidine. Other toxicities included mild nausea and vomiting in all patients, and hypotension and paralytic ileus in one patient each. No cardiac toxicity was observed. One patient had a complete remission and 4 patients had stable disease. We conclude that quinidine and vinblastine may be administered together safely in a clinical setting, with leukopenia being dose-limiting. Further studies are needed to determine any therapeutic advantage over vinblastine alone.