A Phase I Clinical, Pharmacological, and Biological Trial of Interleukin 6 Plus 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 Constitutional Toxicities

A Phase I trial was conducted to determine the safety, biological activity, and hematopoietic recovery by the combination of interleukin 6 (IL-6) and granulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemotherapy in children. Patients <22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m 2 /day × 5 days, carboplatin 400 mg/m 2 /day × 2 days, and etoposide 100 mg/m 2 /day × 5 days, followed by daily s.c. G-CSF (5μ g/kg/day) and IL-6 (2.5, 3.75, or 5.0 μg/kg/day). Pharmacokinetic, proinflammatory mediator levels, hematopoietic colony assays, and cytokine receptor expression studies were performed during course one. Nineteen patients were evaluable for toxicity and received IL-6 at doses of 2.5 ( n = 8), 3.75 ( n = 5), or 5.0 ( n = 6) μg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0μ g/kg/day, two of five patients at 3.75 μg/kg/day, and two of eight patients at 2.5 μg/kg/day. The maximum tolerated dose (MTD) exceeded the lowest dose tested. Because of lack of drug availability, an MTD was not established. The maximum concentration of IL-6 (2.5μ g/kg/day) was 0.799 ± 1.055 ng/ml (mean ± SD). During the first course, the median time to absolute neutrophil count≥ 1,000/mm 3 and platelets ≥100,000 mm 3 was estimated at 19 and 23 days, respectively. Peripheral blood progenitor cells expressing receptors to IL-3, IL-6, and G-CSF increased significantly over baseline ( P < 0.05). After the first dose of IL-6, IFN-γ levels were abnormal in 13 patients, and IL-1β levels were abnormal in 10 patients. IL-6 has a high incidence of constitutional toxicity and a lower MTD in children compared with adults. In vivo use of IL-6 in children after chemotherapy remains limited. However, IL-6 may be more optimally investigated in children under ex vivo conditions.