title: Phase I trial of EpCAM-targeting immunotoxin MOC31PE, alone and in combination with cyclosporin.
abstract: BACKGROUND
  A phase I trial was performed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics and immunogenicity of the anti-EpCAM immunotoxin (IT) MOC31PE in cancer patients. An important part of the study was to investigate whether the addition of Sandimmune (cyclosporin, CsA) suppressed the development of anti-IT antibodies.
  
  
  METHODS
  Patients with EpCAM-positive metastatic disease were eligible for treatment with intravenous MOC31PE using a modified Fibonacci dose escalation sequence. Maximum tolerated dose was first established without, then with intravenously administered CsA.
  
  
  RESULTS
  Sixty-three patients were treated with MOC31PE in doses ranging from 0.5 to 8 μg kg(-1). Maximum tolerated dose was 8 μg kg(-1) for MOC31PE alone, and 6.5 μg kg(-1) when combined with CsA. The dose-limiting adverse event was reversible liver toxicity. No radiological complete or partial responses were observed, whereas stable disease was seen in 36% of the patients receiving MOC31PE only. The pharmacokinetic profile of MOC31PE was characterised by linear kinetics and with a half-life of ∼3 h. The addition of CsA delayed the generation of anti-IT antibodies.
  
  
  CONCLUSIONS
  Intravenous infusion of MOC31PE can safely be administered to cancer patients. Immune suppression with CsA delays the development of anti-MOC31PE antibodies. The antitumour effect of MOC31PE warrants further evaluation in EpCAM-positive metastatic disease.
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.
authors.forename: Y
authors.initials: Y
authors.lastname: Andersson
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.|Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
authors.forename: O
authors.initials: O
authors.lastname: Engebraaten
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Juell
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.|Department of Clinical Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Aamdal
authors.affiliation: Department of Clinical Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.
authors.forename: P
authors.initials: P
authors.lastname: Brunsvig
authors.affiliation: Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, 0424 Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
authors.forename: Ø
authors.initials: Ø
authors.lastname: Fodstad
authors.affiliation: Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Dueland
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001219:Aspartate Aminotransferases / Q000097:blood; D019046:Bone Marrow Neoplasms / Q000188:drug therapy / Q000556:secondary; D002277:Carcinoma / Q000737:chemistry / Q000188:drug therapy / Q000556:secondary; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology; D016572:Cyclosporine / Q000008:administration & dosage; D004347:Drug Interactions; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006207:Half-Life; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects; D007262:Infusions, Intravenous; D007928:Lethal Dose 50; D008252:Macaca fascicularis; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D061206:Neoplasm Micrometastasis; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D018796:Immunoconjugates; C000602279:MOC31PE immunotoxin; D016572:Cyclosporine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase