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

作者：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; Stupp Roger

来源：BMC Cancer, 2013, 13(1): 20.

DOI：10.1186/1471-2407-13-20

• huKS-IL2
• Immunocytokine
• Solid tumors

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. %26lt;br%26gt;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/m(2) on day 1), and escalating doses of huKS-=IL2 (0.5-=4.0 mg/m(2) 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. %26lt;br%26gt;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/m(2) cyclophosphamide was 3.0 mg/m(2). 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. %26lt;br%26gt;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.

• 出版日期2013-1-15