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

Authors

Joseph P Connor, University of Wisconsin, Madison, WI
Mihaela C Cristea, City of Hope, Duarte, CA
Nancy L Lewis, Thomas Jefferson UniversityFollow
Lionel D Lewis, Dartmouth Medical School and Dartmouth–Hitchcock Medical Center, Lebanon, NH
Philip B Komarnitsky, EMD Serono Inc, Rockland, MA
Maria R Mattiacci, Merck Serono S.A. – Geneva, Geneva, Switzerland
Mildred Felder, University of Wisconsin, Madison, WI
Sarah Stewart, University of Wisconsin, Madison, WI
Josephine Harter, University of Wisconsin, Madison, WI
Jean Henslee-Downey, EMD Serono Inc, Rockland, MA
Daniel Kramer, Merck KGaA, Darmstadt, Germany
Roland Neugebauer, Merck KGaA, Darmstadt, Germany
Roger Stupp, University of Lausanne Hospitals (CHUV), Lausanne, SwitzerlandFollow

Document Type

Article

Publication Date

1-1-2013

Comments

This article has been peer reviewed. It was published in: BMC Cancer

2013 Jan 15;13:20.

The published version is available at DOI: 10.1186/1471-2407-13-20. Copyright © BioMed Central

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.

Recommended Citation

Connor, Joseph P; Cristea, Mihaela C; Lewis, Nancy L; Lewis, Lionel D; Komarnitsky, Philip B; Mattiacci, Maria R; Felder, Mildred; Stewart, Sarah; Harter, Josephine; Henslee-Downey, Jean; Kramer, Daniel; Neugebauer, Roland; and Stupp, Roger, "A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors." (2013). Kimmel Cancer Center Faculty Papers. Paper 36.
https://jdc.jefferson.edu/kimmelccfp/36

PubMed ID

23320927