Jill Weisenbach

Clinical and Biological Effects of Recombinant Human Interleukin-18 Administered by Intravenous Infusion to Patients with Advanced Cancer

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 Hodgkins lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 μg/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 μg/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-γ, 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.

A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer

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 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 rhIL-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.

A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3–4 patients were given infusions of rituximab (375 mg/m2) weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B-cell non-Hodgkin lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 &mgr;g/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-&ggr;, GM-CSF, and chemokines were observed after dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.

Tolerability and anti-tumor activity of recombinant human IL-18 (rhIL-18) administered as five daily intravenous infusions in patients with solid tumors.

2553 Background: rhIL-18, a member of the Th-1 inducing family of cytokines, has demonstrated anti-tumor activity in a variety of preclinical tumor models. METHODS In an ongoing phase I dose-escalation study, rhIL-18 (SB485232) was administered as a 2 hour infusion daily for 5 consecutive days to patients (pts) with solid tumors. Doses ranging from 3-1000 μg/kg/day were planned. The objectives were to determine tolerability, define a biologically effective dose, and assess pharmacokinetics, immunogenicity, immunomodulatory and anti-tumor activity of rhIL-18. Pts with detectable anti-SB-485232 antibodies at screening were excluded. RESULTS Twenty-six pts {metastatic renal cell carcinoma (21), advanced melanoma (4), Hodgkins lymphoma (1)}were treated at dose levels up to1000 μg/kg/day . Two pts were withdrawn from the study: 1 pt at 10 μg/kg/day due to rapidly progressive disease and 1 pt at 100 μg/kg/day due to hypotension with bradycardia, a dose-limiting toxicity. This cohort was expanded to 6 pts with no further dose-limiting toxicities. Drug-related adverse event data are available for 25 pts: Grade (G) 1-2 fever (n=19), chills (n=14), rash (n=3) nausea/vomiting (n=8); G1 myalgia (n=3); G1-2 neutropenia (n=11), G1-3 lymphopenia (n=16), G1-2 thrombocytopenia (n=4), G1 elevated AST (n=4), G1-2 elevated ALT (n=5), G1 hypocalcemia (n=3), G1-2 hypoalbuminemia (n=12). Five pts developed antibodies to SB-485232. Increases in neopterin (24/25 pts), GM-CSF (25/25 pts), IL-18 BP (25/25 pts), sFas/L(22/25 pts), and INFγ (15/25 pts) were observed. Upregulation of FasL on NK, CD8+, and CD4+ cells as well as of CD69 on CD8+ cells was observed. Evidence of clinical activity was observed in two patients (metastatic melanoma and renal cell carcinoma) treated at 100 μg/kg/day. CONCLUSIONS rhIL-18 administered as a single cycle was well tolerated. Preliminary data demonstrate evidence of immunomodulatory and clinical activity. [Table: see text].