Abstract
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), Hodgkin's 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 Two pts were withdrawn from the study: 1 pt at 10 μg/kg/day due to rapidly progressive disease and 1 pt at 100 μg/kg/day due to hypotension with bradycardia, a dose-limiting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. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
