Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer.

Michael Robertson, James W. Mier, Theodore Logan, Michael Atkins, Henry Koon, Kevin M. Koch, Steven Kathman, Lini N. Pandite, Coreen Oei, Lyndon C. Kirby, Roxanne C. Jewell, William N. Bell, Linda M. Thurmond, Jill Weisenbach, Suzanne Roberts, Mohammed M. Dar

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Abstract

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.

Original languageEnglish
Pages (from-to)4265-4273
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number14 Pt 1
DOIs
StatePublished - Jul 15 2006

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Interleukin-18
Intravenous Infusions
Neoplasms
Hypotension
Pharmacokinetics
human interleukin 18 protein
Hypoalbuminemia
Chills
Lymphopenia
Fas Ligand Protein
Maximum Tolerated Dose
Hyponatremia
Granulocyte-Macrophage Colony-Stimulating Factor
Bradycardia
Transaminases
Neutropenia
Hodgkin Disease
Renal Cell Carcinoma
Nausea
Headache

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. / Robertson, Michael; Mier, James W.; Logan, Theodore; Atkins, Michael; Koon, Henry; Koch, Kevin M.; Kathman, Steven; Pandite, Lini N.; Oei, Coreen; Kirby, Lyndon C.; Jewell, Roxanne C.; Bell, William N.; Thurmond, Linda M.; Weisenbach, Jill; Roberts, Suzanne; Dar, Mohammed M.

In: Clinical Cancer Research, Vol. 12, No. 14 Pt 1, 15.07.2006, p. 4265-4273.

Research output: Contribution to journalArticle

Robertson, M, Mier, JW, Logan, T, Atkins, M, Koon, H, Koch, KM, Kathman, S, Pandite, LN, Oei, C, Kirby, LC, Jewell, RC, Bell, WN, Thurmond, LM, Weisenbach, J, Roberts, S & Dar, MM 2006, 'Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer.', Clinical Cancer Research, vol. 12, no. 14 Pt 1, pp. 4265-4273. https://doi.org/10.1158/1078-0432.CCR-06-0121
Robertson, Michael ; Mier, James W. ; Logan, Theodore ; Atkins, Michael ; Koon, Henry ; Koch, Kevin M. ; Kathman, Steven ; Pandite, Lini N. ; Oei, Coreen ; Kirby, Lyndon C. ; Jewell, Roxanne C. ; Bell, William N. ; Thurmond, Linda M. ; Weisenbach, Jill ; Roberts, Suzanne ; Dar, Mohammed M. / Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 14 Pt 1. pp. 4265-4273.
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abstract = "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.",
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AU - Robertson, Michael

AU - Mier, James W.

AU - Logan, Theodore

AU - Atkins, Michael

AU - Koon, Henry

AU - Koch, Kevin M.

AU - Kathman, Steven

AU - Pandite, Lini N.

AU - Oei, Coreen

AU - Kirby, Lyndon C.

AU - Jewell, Roxanne C.

AU - Bell, William N.

AU - Thurmond, Linda M.

AU - Weisenbach, Jill

AU - Roberts, Suzanne

AU - Dar, Mohammed M.

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N2 - 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.

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