Clinical and pharmacokinetic studies of high-dose levamisole in combination with 5-fluorouracil in patients with advanced cancer

Purpose: To determine the maximum tolerable dose (MTD) and activity of levamisole administered concurrently with 5-fluorouracil (5-FU) in a standard 5-day course. To determine the pharmacokinetics of levamisole during the course of treatment. Patients and methods: Levamisole was administered to 38 patients orally three times a day for 5 days concurrently with a course of 5-FU administered daily by rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who received escalating doses of levamisole. The activity of the combination was evaluated in 18 patients who received levamisole at the MTD with 5-FU. The pharmacokinetics of levamisole were characterized in ten patients at the MTD level. Results: Intractable vomiting, confusion and vertigo were the major dose-limiting toxicities. The MTD of oral levamisole was 100 mg/m² administered three times a day concurrently with 450 mg/m² per day intravenous 5-FU for 5 consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18 patients with measurable disease at the MTD. Peak plasma concentrations of 1 μg/ml (range 0.6-1.3 μg/ml) were achieved 90 min (range 60-360 min) after an oral dose of 100 mg/m² levamisole with a 3.5-fold accumulation noted following 4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were about 5% of parent drug. Little parent drug (2-5%) was detected in urine. Conclusions: Levamisole may be administered safely with 5-FU at doses which are up to four to five times greater than those presently given in conventional regimens. The recommended dose of levamisole combined with 5-FU for future research protocols is 75 mg/m² t.i.d for 5 days.