Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies.

Abstract

Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ) following intrathecal administration in patients with refractory meningeal malignancies. Thirty-nine patients received 45 courses of intrathecal AZQ. Two schedules were studied; twice-weekly administration of a 1- or 2-mg dose and "concentration times time" (C x T) administration of 0.5 mg every 6 hours for three doses, administered once weekly. Dose-limiting toxicity consisting of headache, nausea, or vomiting occurred in only three patients and only at the 2-mg, twice weekly dose. The schedules of 1 mg twice-weekly and 0.5 mg every 6 hours for three doses were well tolerated. Thirty-seven courses were assessable for response. The overall response rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses (38%) and partial responses (PRs) occurred in nine of 37 courses (24%). Among patients with meningeal leukemia, CRs were observed in 11 of 26 courses (42%) and PRs in nine of 26 courses (35%). There was no difference in response rate related to dose or schedule. The pharmacokinetic behavior of intrathecally administered AZQ was characterized by biexponential disappearance from ventricular CSF, with mean half-lives of 18.2 and 78.6 minutes. The mean clearance rate was 0.37 mL/min. Intrathecal AZQ is safe, well tolerated, and highly active against refractory meningeal malignancies.