A phase I clinical, pharmacological, and biological trial of interleukin 6plus granulocyte-colony stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent/refractory solid tumors: Enhanced hematological responses but a high incidence of grade III/IV constitutionaltoxicities

Phase I trial was conducted to determine the safety, biological activity, a nd hematopoietic recovery by the combination of interleukin 6 (IL-6) and gr anulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemothe rapy in children. Patients <22 years of age at diagnosis with either recurr ent or refractory solid tumors received ifosfamide 1,800 mg/m(2)/day x 5 da ys, carboplatin 400 mg/m(2)/day x 2 days, and etoposide 100 mg/m(2)/day x 5 days, followed by daily s.c. G-CSF (5 <mu>g/kg/day) and IL-6 (2.5, 3.75, o r 5.0 mug/kg/day), Pharmacokinetic, proinflammatory mediator levels, hemato poietic colony assays, and cytokine receptor expression studies were perfor med during course one. Nineteen patients were evaluable for toxicity and re ceived IL-6 at doses of 2.5 (n = 8), 3.75 (n = 5), or 5.0 (n = 6) mug/kg/da y. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 mug/kg/day, two of five patients at 3.75 mug/kg/day, and two of eight patients at 2.5 mug/kg/day. The maximum tolerated dose (MTD) exceeded the l owest dose tested. Because of lack of drug availability, an MTD was not est ablished. The maximum concentration of IL-6 (2.5 mug/kg/day) was 0.799 +/- 1.055 ng/ml (mean +/- SD). During the first course, the median time to abso lute neutrophil count greater than or equal to1,000/mm(3) and platelets gre ater than or equal to 100,000 mm(3) was estimated at 19 and 23 days, respec tively. Peripheral blood progenitor cells expressing receptors to IL-3, IL- 6, and GCSF increased significantly over baseline (P < 0.05). After the fir st dose of IL-6, IFN-<gamma> levels were abnormal in 13 patients, and IL-1 beta levels were abnormal in 10 patients, IL-6 has a high incidence of cons titutional toxicity and a lower MTD in children compared with adults. In vi vo use of IL-6 in children after chemotherapy remains limited. However, IL- 6 may be more optimally investigated in children under ex vivo conditions.