title: A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.
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.
  
  
  CONCLUSIONS
  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.
authors: University of Wisconsin, Madison, WI 53706, USA. jconnor361@gmail.com
authors: Joseph P
authors: JP
authors: Connor
authors: Mihaela C
authors: MC
authors: Cristea
authors: Nancy L
authors: NL
authors: Lewis
authors: Lionel D
authors: LD
authors: Lewis
authors: Philip B
authors: PB
authors: Komarnitsky
authors: Maria R
authors: MR
authors: Mattiacci
authors: Mildred
authors: M
authors: Felder
authors: Sarah
authors: S
authors: Stewart
authors: Josephine
authors: J
authors: Harter
authors: Jean
authors: J
authors: Henslee-Downey
authors: Daniel
authors: D
authors: Kramer
authors: Roland
authors: R
authors: Neugebauer
authors: Roger
authors: R
authors: Stupp
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007376:Interleukin-2; C494047:tucotuzumab celmoleukin; D003520:Cyclophosphamide