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 pharmacok inetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF. Patients and m ethods: Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administere d at doses of 12, 21, 28, 32, 37, and 48 mg/m(2) on day 1; GM-CSF (5 m u g/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 w ere assayed for mitoxantrone concentrations using high performance liq uid chromatography (HPLC). Results. Twelve patients required either mi toxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m(2)/day. Therefore, we conclude the M TD was 37 mg/m(2)/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricu lar ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone l evels increased linearly with dose; triexponential elimination of mito xantrone was observed. No statistically significant correlation was ob served between either peak mitoxantrone level or AUC and duration of a bsolute neutrophil count(ANC) <500/mm(3). Conclusion: The use of GM-CS F allows administration of mitoxantrone at a dose greater than three t imes that given in standard therapy; treatment is well tolerated. Furt her studies are needed to determine whether mitoxantrone has cumulativ e cardiac or hematologic toxicity.