Phase I study of a 5-day schedule of mitoxantrone (dihydroxyanthracenedione).

Mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride) in animal studies appears to have a mechanism of action and broad antitumor spectrum similar to the anthracyclines and in preliminary animal studies is without cardiotoxicity. To determine the maximally tolerated dose, mitoxantrone was given to 25 patients with various advanced solid tumors. Sixteen patients had received prior doxorubicin and/or lomustine (CCNU). Myelosuppression was the major toxic effect. All 13 patients who received mitoxantrone doses greater than or equal to 2.73 mg/m2 x 5 days experienced moderate (2000--3000 cells/mm3) or severe (less than 2000 cells/mm3) leukopenia. Thrombocytopenia was also encountered in three of these 13 patients (severe in one, less than 50,000 cells/mm3). At dose levels less than 2.73 mg/m2 x 5 days, myelosuppression was seen in four of 12 patients (three with mild leukopenia and one with mild thrombocytopenia). The blood cell count nadir occurred at 10 days and full recovery occurred by Day 21. Minor clinically insignificant ECG changes occurred in five patients. Minor and transient antitumor effects were seen in five patients. The maximum tolerated dose of mitoxantrone over a 5-day course is 2.73 mg/m2, with leukopenia being the limiting toxic effect.