title: 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.
abstract: 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/m2/day x 5 days, carboplatin 400 mg/m2/ day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily s.c. G-CSF (5 microg/kg/day) and IL-6 (2.5, 3.75, or 5.0 microg/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) microg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 microg/kg/day, two of five patients at 3.75 microg/kg/day, and two of eight patients at 2.5 microg/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 (2.5 microg/kg/day) was 0.799 +/- 1.055 ng/ml (mean +/- SD). During the first course, the median time to absolute neutrophil count > or = 1,000/mm3 and platelets > or = 100,000 mm3 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-gamma levels were abnormal in 13 patients, and IL-1beta 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.
authors.affiliation: Lombardi Cancer Center, Georgetown University Hospital, Washington, DC 20007, USA.
authors.forename: F
authors.initials: F
authors.lastname: Bracho
authors.forename: M D
authors.initials: MD
authors.lastname: Krailo
authors.forename: V
authors.initials: V
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Bergeron
authors.forename: V
authors.initials: V
authors.lastname: Davenport
authors.forename: W
authors.initials: W
authors.lastname: Liu-Mares
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: A
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: C
authors.initials: C
authors.lastname: van de Ven
authors.forename: R
authors.initials: R
authors.lastname: Secola
authors.forename: M M
authors.initials: MM
authors.lastname: Ames
authors.forename: J M
authors.initials: JM
authors.lastname: Reid
authors.forename: G H
authors.initials: GH
authors.lastname: Reaman
authors.forename: M S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005047:Etoposide / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009369:Neoplasms / Q000503:physiopathology / Q000628:therapy*; D011994:Recombinant Proteins
chemical_list: D015850:Interleukin-6; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D016190:Carboplatin; D007069:Ifosfamide