PMID- 16857801
OWN - NLM
STAT- MEDLINE
DCOM- 20070126
LR  - 20210102
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 14 Pt 1
DP  - 2006 Jul 15
TI  - Clinical and biological effects of recombinant human interleukin-18 administered 
      by intravenous infusion to patients with advanced cancer.
PG  - 4265-73
AB  - PURPOSE: 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. EXPERIMENTAL DESIGN: 
      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.
FAU - Robertson, Michael J
AU  - Robertson MJ
AD  - Lymphoma Program, Indiana University School of Medicine, Indianapolis, Indiana 
      46202, USA. mjrobert@iupui.edu
FAU - Mier, James W
AU  - Mier JW
FAU - Logan, Theodore
AU  - Logan T
FAU - Atkins, Michael
AU  - Atkins M
FAU - Koon, Henry
AU  - Koon H
FAU - Koch, Kevin M
AU  - Koch KM
FAU - Kathman, Steven
AU  - Kathman S
FAU - Pandite, Lini N
AU  - Pandite LN
FAU - Oei, Coreen
AU  - Oei C
FAU - Kirby, Lyndon C
AU  - Kirby LC
FAU - Jewell, Roxanne C
AU  - Jewell RC
FAU - Bell, William N
AU  - Bell WN
FAU - Thurmond, Linda M
AU  - Thurmond LM
FAU - Weisenbach, Jill
AU  - Weisenbach J
FAU - Roberts, Suzanne
AU  - Roberts S
FAU - Dar, Mohammed M
AU  - Dar MM
LA  - eng
GR  - RR00750-27S3/RR/NCRR NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-18)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Area Under Curve
MH  - Carcinoma, Renal Cell/drug therapy
MH  - Cohort Studies
MH  - Cytokines/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Hodgkin Disease/drug therapy
MH  - Humans
MH  - Infusions, Intravenous
MH  - Interleukin-18/*administration & dosage
MH  - Male
MH  - Melanoma/drug therapy
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/*metabolism
MH  - Recombinant Proteins/*administration & dosage
EDAT- 2006/07/22 09:00
MHDA- 2007/01/27 09:00
CRDT- 2006/07/22 09:00
PHST- 2006/07/22 09:00 [pubmed]
PHST- 2007/01/27 09:00 [medline]
PHST- 2006/07/22 09:00 [entrez]
AID - 12/14/4265 [pii]
AID - 10.1158/1078-0432.CCR-06-0121 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4265-73. doi: 
      10.1158/1078-0432.CCR-06-0121.