A study of amsalog (CI-921) administered orally on a 5-day schedule, with bioavailability and pharmacokinetically...

Amsalog is a derivative of 9-aminoacridine. Phase I studies using intravenous (i.v.) amsalog have shown the dose-limiting toxicity (DLT) to be phlebitis and myelosuppression. Phase II studies using a variety of schedules have shown evidence of activity in patients with large-cell lung, breast, and head and neck cancers. Preclinical studies demonstrated that amsalog is active orally: a clinical study of the oral bioavailability of amsalog was therefore performed.

A group of 20 patients with refractory malignancies were treated. There were two phases of the study: a pharmacokinetic comparison of i.v. against oral amsalog, followed by a pharmacokinetically guided oral dose escalation study. In the first phase of the study, 11 patients were treated. Amsalog 50 mg/m2 was administered i.v., and 50 mg/m2 and 200 mg/m2 orally. In the second phase of the study, 9 patients were treated in three cohorts of three. On day 1 of a 5-day schedule, amsalog was administered i.v. at the maximum tolerated dose (MTD) of 200 mg/m2. Subsequent doses were given orally, starting at a dose of 200 mg/m2 per day, with intrapatient dose escalation of up to 100% for the second cycle. Doses were escalated further in subsequent cohorts, based on oral bioavailability and toxicity.

Oral bioavailability of 50 mg/m2 amsalog was 34%. In the dose escalation phase, DLT was neutropenia; other toxicities included malaise and nausea. The MTD was 1600 mg/m2 per day for 5 days. The plasma AUC using 1600 mg/m2 by the oral route was higher than that achieved using 200 mg/m2 by the i.v. route.

Amsalog can be tolerated orally on a 5-day schedule at doses up to 1600 mg/m2. The recommended dose for further evaluation is 800 mg/m2 daily for 5 days, repeated three weekly.