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

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.

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 micrograms/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).

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 Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF).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.

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.