title: Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer.
abstract: BACKGROUND
  A novel immunological approach to colon cancer therapy is the antibody targeting of the fibroblast activation protein (FAP), which is highly expressed by stroma cells of this tumour. Unconjugated sibrotuzumab (BIBH 1), which is a humanised version of the murine anti-FAP mAb F19, was investigated for its anti-tumour activity, safety and pharmacokinetics.
  
  
  METHODS
  Patients with metastatic colorectal cancer received weekly intravenous infusions of unconjugated sibrotuzumab at a dose of 100 mg over 12 scheduled weeks. The study was implemented as an open-label, uncontrolled, multicentre trial.
  
  
  RESULTS
  25 patients were enrolled. Patients had one or more measurable lesions, predominantly liver lesions, at baseline. At least 8 repeated weekly infusions of sibrotuzumab in 17 evaluable patients did not result in complete or partial remission. Rather, ongoing tumour progression was noted in all patients except for 2 patients with stable disease. However, progressive disease was also observed post-study in these 2 patients who received 1 and 6 additional infusions, respectively, of sibrotuzumab. Sibrotuzumab exhibited 2-compartment pharmacokinetics with a dominant terminal phase and t1/2 beta = 5.3 +/- 2.3 days. Adverse drug reactions (rigors/chills, nausea, flushing and one incidence of bronchospasm) were observed in 5 patients. Of the 24 patients given 2 or more infusions of sibrotuzumab, antibodies against sibrotuzumab were found in 3 patients (12.5%) after 4-12 infusions.
  
  
  CONCLUSIONS
  Sibrotuzumab was well tolerated and safe. The minimal requirement for the continuation of this exploratory trial, of at least one complete or partial remission, or equivalently, of 4 patients with stable disease, was not met.
authors.affiliation: Onkologisches Zentrum, III. Medizinische Klinik, Universitätsklinikum Mannheim, Germany. ralf.hofheinz@med3.ma.uni-heidelberg.de
authors.forename: R-D
authors.initials: RD
authors.lastname: Hofheinz
authors.forename: S-E
authors.initials: SE
authors.lastname: al-Batran
authors.forename: F
authors.initials: F
authors.lastname: Hartmann
authors.forename: G
authors.initials: G
authors.lastname: Hartung
authors.forename: D
authors.initials: D
authors.lastname: Jäger
authors.forename: C
authors.initials: C
authors.lastname: Renner
authors.forename: P
authors.initials: P
authors.lastname: Tanswell
authors.forename: U
authors.initials: U
authors.lastname: Kunz
authors.forename: A
authors.initials: A
authors.lastname: Amelsberg
authors.forename: H
authors.initials: H
authors.lastname: Kuthan
authors.forename: G
authors.initials: G
authors.lastname: Stehle
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D010450:Endopeptidases; D005260:Female; D005500:Follow-Up Studies; D018093:Gelatinases; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary*; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010166:Palliative Care; D012697:Serine Endopeptidases; D016896:Treatment Outcome; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C476229:sibrotuzumab