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

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• 作者：Joseph P Connor (1)
  Mihaela C Cristea (2)
  Nancy L Lewis (3)
  Lionel D Lewis (4)
  Philip B Komarnitsky (5)
  Maria R Mattiacci (6) (9)
  Mildred Felder (1)
  Sarah Stewart (1)
  Josephine Harter (1)
  Jean Henslee-Downey (5)
  Daniel Kramer (7)
  Roland Neugebauer (7)
  Roger Stupp (8)
  
• 关键词：huKS ; IL2 ; Immunocytokine ; Solid tumors
• 刊名：BMC Cancer
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：13
• 期：1
• 全文大小：456KB
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  29. The pre-publication history for this paper can be accessed here:1471-2407/13/20/prepub" class="a-plus-plus">http://www.biomedcentral.com/1471-2407/13/20/prepub
  
• 作者单位：Joseph P Connor (1)
  Mihaela C Cristea (2)
  Nancy L Lewis (3)
  Lionel D Lewis (4)
  Philip B Komarnitsky (5)
  Maria R Mattiacci (6) (9)
  Mildred Felder (1)
  Sarah Stewart (1)
  Josephine Harter (1)
  Jean Henslee-Downey (5)
  Daniel Kramer (7)
  Roland Neugebauer (7)
  Roger Stupp (8)
  
  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
  9. Presently at Actelion Pharmaceutical Ltd, Allschwil, Switzerland
  7. Merck KGaA, Darmstadt, Germany
  8. University of Lausanne Hospitals (CHUV), Lausanne, Switzerland
  
• ISSN：1471-2407

文摘

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-.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 NCT00132522