Phase I and Clinical Pharmacology Studies of Intravenous and Oral Administration of 4-Demethoxydaunorubicin in Patients with Advanced Cancer1

4-Demethoxydaunorubicin (4-DMDR), an anthracycline ana logue available in i.v. and p.o. form, has shown significant antitumor activity in murine tumor models while producing less cardiac toxicity than doxorubicin at equimyelotoxic doses. Phase I and clinical pharmacology studies of the i.v. and p.o. preparation were performed. With i.v. 4-DMDR, consistent myelosuppression was observed at a dose of 15 mg/sq m at a median Day 15; mild nausea and vomiting were observed in 9% of all treatment courses. In patients given p.o. 4-DMDR, myelosuppression oc curred at median Day 14 in 10 of 12 patients given 50 mg/sq m. Nausea and vomiting occurred in 25% of all treatment courses, and dividing the dose over 3 days did not decrease the incidence. Alopecia occurred in 13% of évaluablepatients treated with the i.v. preparation and 30% of évaluablepatients treated p.o. No stomatitis was observed with either preparation, and no patient developed clinical signs of congestive heart failure. Pharmacokinetic studies were performed with both preparations and re vealed prolonged plasma levels of the 13-hydroxy metabolite 4DMDR-ol. The suggested starting dose for Phase II studies is 12.5 mg/sq m given every 21 days for i.v. 4-DMDR with dose escalation by 2.5 mg/sq m in the absence of myelotoxicity. For p.o. 4-DMDR, the suggested starting dose is 40 mg/sq m given every 21 days with escalation by 10 mg/sq m if no myelotoxicity is observed.