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

Clin Cancer Res. 2001 Jan;7(1):58-67.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / adverse effects
  • Carboplatin / therapeutic use*
  • Child
  • Child, Preschool
  • Enzyme-Linked Immunosorbent Assay
  • Etoposide / adverse effects
  • Etoposide / therapeutic use*
  • Female
  • Granulocyte Colony-Stimulating Factor / adverse effects
  • Granulocyte Colony-Stimulating Factor / therapeutic use*
  • Hematopoietic Stem Cells / drug effects
  • Humans
  • Ifosfamide / adverse effects
  • Ifosfamide / therapeutic use*
  • Infant
  • Infusions, Intravenous
  • Interleukin-6 / adverse effects
  • Interleukin-6 / therapeutic use*
  • Male
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Neoplasms / physiopathology
  • Neoplasms / therapy*
  • Recombinant Proteins

Substances

  • Interleukin-6
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • Etoposide
  • Carboplatin
  • Ifosfamide

Supplementary concepts

  • ICE protocol 3