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A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer

Authors' Affiliations: ¹ Lymphoma Program and ² Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; ³ Melanoma and Skin Cancer Program of the Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁴ GlaxoSmithKline, Inc., Research Triangle Park, North Carolina

Requests for reprints: Michael J. Robertson, Division of Hematology/Oncology, Indiana University School of Medicine, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202. Phone: 317-278-6942; Fax: 317-278-4190; E-mail: mjrobert{at}iupui.edu.

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 administered at different doses in two different schedules to patients with advanced cancer.

Experimental Design: Cohorts of three to four patients were given escalating doses of rhIL-18 as a 2-h i.v. infusion either on 5 consecutive days repeated every 28 days (group A) or once a week (group B) for up to 6 months. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic measurements.

Results: Nineteen patients (10 melanoma and 9 renal cell cancer) were given rhIL-18 in doses of 100, 500, or 1,000 µg/kg (group A) or 100, 1,000, or 2,000 µg/kg (group B). Common side effects included chills, fever, headache, fatigue, and nausea. Common laboratory abnormalities included transient, asymptomatic grade 1 to 3 lymphopenia, grade 1 to 4 hyperglycemia, grade 1 to 2 anemia, neutropenia, hypoalbuminemia, liver enzyme elevations, and serum creatinine elevations. No dose-limiting toxicities were observed. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-, granulocyte macrophage colony-stimulating factor, and IL-18–binding protein were observed following dosing.

Conclusions: rhIL-18 can be given in biologically active doses by either weekly infusions or daily infusions for 5 days repeated every 28 days to patients with advanced cancer. Toxicity was generally mild to moderate, and a maximum tolerated dose of rhIL-18 by either schedule was not determined.