In the human clonogenic assay, mitoxantrone possesses among the steepest dose-response curves of any cytotoxic agent against ovarian cancer. To test the potential clinical relevance of this observation, we conducted a phase 2 trial of moderately high dose single agent mitoxantrone (28 mg/m2 delivered every 3-4 weeks) along with granulocyte-macrophage colony stimulating factor (250 micrograms/m2/day beginning 24 h after mitoxantrone and continuing until neutrophil recovery) in 34 patients with clinically defined platinum and paclitaxel-refractory ovarian cancer. The major toxicity of treatment was severe neutropenia which was almost universal. However, there were no treatment-related infectious deaths. Significant cardiac toxicity was not observed. Five of 33 evaluable patients demonstrated objective evidence of a response to treatment (1 patient achieving a partial response of measurable tumor masses, 4 patients achieving a > or = 50% reduction in CA-125 antigen level), with a median duration of response of 3 months (range 2-5 months). We conclude that moderately high dose mitoxantrone has definite, although very limited, single agent activity in platinum and paclitaxel-refractory ovarian cancer. Unfortunately, as this regimen produces severe hematologic toxicity and response durations are short, it cannot be recommended for routine clinical use. The role of an even higher dose mitoxantrone schedule employed as a component of a high dose chemotherapy program with bone marrow or peripheral progenitor cell protection in the treatment of ovarian cancer remains to be defined.