A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

Joseph P. Connor*, Mihaela C. Cristea, Nancy L. Lewis, Lionel D. Lewis, Philip B. Komarnitsky, Maria R. Mattiacci, Mildred Felder, Sarah Stewart, Josephine Harter, Jean Henslee-Downey, Daniel Kramer, Roland Neugebauer, Roger Stupp

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Background: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent.Methods: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated.Results: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients.Conclusion: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.Trial registration: http://NCT00132522.

Original languageEnglish (US)
Article number20
JournalBMC cancer
Volume13
DOIs
StatePublished - Jan 15 2013

Keywords

  • Immunocytokine
  • Solid tumors
  • huKS-IL2

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

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    Connor, J. P., Cristea, M. C., Lewis, N. L., Lewis, L. D., Komarnitsky, P. B., Mattiacci, M. R., Felder, M., Stewart, S., Harter, J., Henslee-Downey, J., Kramer, D., Neugebauer, R., & Stupp, R. (2013). A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors. BMC cancer, 13, [20]. https://doi.org/10.1186/1471-2407-13-20