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, 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

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: ClinicalTrials.gov NCT00132522.

Figures

Figure 1
Figure 1
Mean (standard deviation) serum concentration profiles on day 2 of cycle 1.
Figure 2
Figure 2
Dose–response relationship of huKS-IL2. Day 2, cycle 1, as shown by Cmax(a) and AUC0–24h(b). Cmax, maximum or peak serum concentration; AUC0–24h, area under the concentration versus time curve from time zero to 24 hours after the start of infusion.
Figure 3
Figure 3
Serum levels of antibodies over time. (a) Anti-idiotype antibodies; (b) anti-Fc-IL2 antibodies; and (c) anti-IL2 antibodies.
Figure 4
Figure 4
Immune cell monitoring. Cytotoxic natural killer cells (a); CD4+ T-cells (b); CD8+ T-cells (c); and T-reg cells (d). C1D1, cycle 1 day 1; C1D2, cycle 2 day 2, etc.
Figure 5
Figure 5
Kaplan–Meier plot of overall survival. * The Kaplan–Meier method was applied only for dose-level groups with at least 6 patients.

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