TY - JOUR
T1 - A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors
AU - Connor, Joseph P.
AU - Cristea, Mihaela C.
AU - Lewis, Nancy L.
AU - Lewis, Lionel D.
AU - Komarnitsky, Philip B.
AU - Mattiacci, Maria R.
AU - Felder, Mildred
AU - Stewart, Sarah
AU - Harter, Josephine
AU - Henslee-Downey, Jean
AU - Kramer, Daniel
AU - Neugebauer, Roland
AU - Stupp, Roger
N1 - Funding Information:
The trial was sponsored by EMD Serono Inc., Rockland, MA, USA. The authors would like to thank the patients and their families, without whom this study would not have been possible. Medical writing and editorial assistance in the preparation of this manuscript was provided by Sandra Mendes, PhD, TRM Oncology, The Hague, The Netherlands, funded by EMD Serono Inc., Rockland, MA, USA. The immunocytokine huKS-IL2 is in clinical development and is not currently approved by any regulatory authority, including the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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.
AB - 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.
KW - Immunocytokine
KW - Solid tumors
KW - huKS-IL2
UR - http://www.scopus.com/inward/record.url?scp=84872135803&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872135803&partnerID=8YFLogxK
U2 - 10.1186/1471-2407-13-20
DO - 10.1186/1471-2407-13-20
M3 - Article
C2 - 23320927
AN - SCOPUS:84872135803
SN - 1471-2407
VL - 13
JO - BMC Cancer
JF - BMC Cancer
M1 - 20
ER -
