Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia.

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.