title: Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer.
abstract: 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.
authors.affiliation: Lymphoma Program, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. mjrobert@iupui.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.forename: Theodore
authors.initials: T
authors.lastname: Logan
authors.forename: Michael
authors.initials: M
authors.lastname: Atkins
authors.forename: Henry
authors.initials: H
authors.lastname: Koon
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
authors.forename: Steven
authors.initials: S
authors.lastname: Kathman
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
authors.forename: Coreen
authors.initials: C
authors.lastname: Oei
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Kirby
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Jewell
authors.forename: William N
authors.initials: WN
authors.lastname: Bell
authors.forename: Linda M
authors.initials: LM
authors.lastname: Thurmond
authors.forename: Jill
authors.initials: J
authors.lastname: Weisenbach
authors.forename: Suzanne
authors.initials: S
authors.lastname: Roberts
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Dar
mesh_terms: 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*
chemical_list: D016207:Cytokines; D020382:Interleukin-18; D011994:Recombinant Proteins