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

Michael Robertson, John M. Kirkwood, Theodore Logan, Kevin M. Koch, Steven Kathman, Lyndon C. Kirby, William N. Bell, Jill Weisenbach, Linda M. Thurmond, Mohammed M. Dar

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Purpose: lnterleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhlL-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. Experimental Design: 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 rhlL-18 in closes of 100, 500, or 1,000 μg/kg (group A) or 100,1,000, or 2,000 μg/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 rh IL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, 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.

Original languageEnglish
Pages (from-to)3462-3469
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2008

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Appointments and Schedules
Lymphopenia
Interleukin-18
Pharmacokinetics
Hypoalbuminemia
Neoplasms
Chills
Maximum Tolerated Dose
Granulocyte-Macrophage Colony-Stimulating Factor
Neutropenia
Serum
Renal Cell Carcinoma
Hyperglycemia
Nausea
Fatigue
Headache
Anemia
Melanoma
Creatinine
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A dose-escalation study of recombinant human Lnterleukin-18 using two different schedules of administration in patients with cancer. / Robertson, Michael; Kirkwood, John M.; Logan, Theodore; Koch, Kevin M.; Kathman, Steven; Kirby, Lyndon C.; Bell, William N.; Weisenbach, Jill; Thurmond, Linda M.; Dar, Mohammed M.

In: Clinical Cancer Research, Vol. 14, No. 11, 01.06.2008, p. 3462-3469.

Research output: Contribution to journalArticle

Robertson, Michael ; Kirkwood, John M. ; Logan, Theodore ; Koch, Kevin M. ; Kathman, Steven ; Kirby, Lyndon C. ; Bell, William N. ; Weisenbach, Jill ; Thurmond, Linda M. ; Dar, Mohammed M. / A dose-escalation study of recombinant human Lnterleukin-18 using two different schedules of administration in patients with cancer. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 11. pp. 3462-3469.
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abstract = "Purpose: lnterleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhlL-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. Experimental Design: 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 rhlL-18 in closes of 100, 500, or 1,000 μg/kg (group A) or 100,1,000, or 2,000 μg/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 rh IL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, 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.",
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T1 - A dose-escalation study of recombinant human Lnterleukin-18 using two different schedules of administration in patients with cancer

AU - Robertson, Michael

AU - Kirkwood, John M.

AU - Logan, Theodore

AU - Koch, Kevin M.

AU - Kathman, Steven

AU - Kirby, Lyndon C.

AU - Bell, William N.

AU - Weisenbach, Jill

AU - Thurmond, Linda M.

AU - Dar, Mohammed M.

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N2 - Purpose: lnterleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhlL-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. Experimental Design: 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 rhlL-18 in closes of 100, 500, or 1,000 μg/kg (group A) or 100,1,000, or 2,000 μg/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 rh IL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, 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.

AB - Purpose: lnterleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. A phase I study of recombinant human IL-18 (rhlL-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. Experimental Design: 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 rhlL-18 in closes of 100, 500, or 1,000 μg/kg (group A) or 100,1,000, or 2,000 μg/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 rh IL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, 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.

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