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Open Access Research article

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

Joseph P Connor1*, Mihaela C Cristea2, Nancy L Lewis3, Lionel D Lewis4, Philip B Komarnitsky5, Maria R Mattiacci69, Mildred Felder1, Sarah Stewart1, Josephine Harter1, Jean Henslee-Downey5, Daniel Kramer7, Roland Neugebauer7 and Roger Stupp8

Author Affiliations

1 University of Wisconsin, Madison, WI, 53706, USA

2 City of Hope, Duarte, CA, USA

3 Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, USA

4 Department of Medicine and The Norris Cotton Cancer Center, Dartmouth Medical School and Dartmouth–Hitchcock Medical Center, Lebanon, NH, USA

5 EMD Serono Inc, Rockland, MA, USA

6 Merck Serono S.A. – Geneva, Geneva, Switzerland

7 Merck KGaA, Darmstadt, Germany

8 University of Lausanne Hospitals (CHUV), Lausanne, Switzerland

9 Presently at Actelion Pharmaceutical Ltd, Allschwil, Switzerland

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BMC Cancer 2013, 13:20  doi:10.1186/1471-2407-13-20

Published: 15 January 2013

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 webcite

Keywords:
huKS-IL2; Immunocytokine; Solid tumors