Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer.
OBJECTIVE
Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal 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 in patients with advanced cancer.


METHODS
Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements.


RESULTS
Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 microg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 microg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-gamma, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment.


CONCLUSIONS
rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.
Robertson
Michael J
MJ
Lymphoma Program, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. mjrobert@iupui.edu
Mier
James W
JW
Logan
Theodore
T
Atkins
Michael
M
Koon
Henry
H
Koch
Kevin M
KM
Kathman
Steven
S
Pandite
Lini N
LN
Oei
Coreen
C
Kirby
Lyndon C
LC
Jewell
Roxanne C
RC
Bell
William N
WN
Thurmond
Linda M
LM
Weisenbach
Jill
J
Roberts
Suzanne
S
Dar
Mohammed M
MM
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy; D006801:Humans; D007262:Infusions, Intravenous; D020382:Interleukin-18 / Q000008:administration & dosage*; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage*
D016207:Cytokines; D020382:Interleukin-18; D011994:Recombinant Proteins