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Clinical Trial
. 2008 Jun 1;14(11):3462-9.
doi: 10.1158/1078-0432.CCR-07-4740.

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

Michael J Robertson  1 , John M Kirkwood, Theodore F Logan, Kevin M Koch, Steven Kathman, Lyndon C Kirby, William N Bell, Linda M Thurmond, Jill Weisenbach, Mohammed M Dar
Affiliations
Clinical Trial

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

Michael J Robertson et al. Clin Cancer Res. .

Abstract

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical 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 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 rhIL-18 in doses of 100, 500, or 1,000 microg/kg (group A) or 100, 1,000, or 2,000 microg/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 rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-gamma, 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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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

K. Koch, L. Kirby, W. Bell, and M. Dar are employed by GlaxoSmithKline. M. Robertson received a research grant from GlaxoSmithKline and has a financial interest in Eli Lilly Corporation. The other authors have disclosed no potential conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Representative median plasma rhIL-18 concentration versus time profiles spanning the dose range, showing the similarity in systemic exposure over time, from day 1 of cycle 1 to day 1 of cycle 2 (group A) and from week 1 to week 4 (group B).
Fig. 2.
Fig. 2.
Attenuation of granulocyte macrophage colony-stimulating factor (GM-CSF; A) and IFN-γ response (B) to 32 weekly doses of rhIL-18 in individual patients (group B).
Fig. 3.
Fig. 3.
Induction and persistence of IL-18 BP represented by predose and 24-h postdose concentrations on day 1 of cycles 1 and 2 (group A) and weeks 1 and 4 (group B) at all doses.
Fig. 4.
Fig. 4.
Change in circulating CD69+ natural killer (NK) cell count relative to predose at all doses.
See this image and copyright information in PMC

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