Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

Purpose: To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. Patients and methods: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m² on day 1; GM-CSF (5 Μg/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC). Results: Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m²/day. Therefore, we conclude the MTD was 37 mg/m²/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm³. Conclusion: The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.