A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer.
OBJECTIVE
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.


METHODS
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 microg/kg (group A) or 100, 1,000, or 2,000 microg/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-gamma, 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.
Lymphoma Program, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, USA. mjrobert@iupui.edu
Michael J
MJ
Robertson
John M
JM
Kirkwood
Theodore F
TF
Logan
Kevin M
KM
Koch
Steven
S
Kathman
Lyndon C
LC
Kirby
William N
WN
Bell
Linda M
LM
Thurmond
Jill
J
Weisenbach
Mohammed M
MM
Dar
D000368:Aged; D000906:Antibodies / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics
D000906:Antibodies; D000970:Antineoplastic Agents; D020382:Interleukin-18; D011994:Recombinant Proteins