title: Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer.
abstract: BACKGROUND
  Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1).
  
  
  METHODS
  This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg(-1) every 14 days), followed by maintenance therapy with 10 mg kg(-1) infused every 14 days.
  
  
  RESULTS
  A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab.
  
  
  CONCLUSIONS
  No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.
authors.affiliation: Department of Medicine (Cancer Research), West German Cancer Centre, University Hospital Essen, Essen 45122, Germany. tanja.trarbach@uk-essen.de
authors.forename: T
authors.initials: T
authors.lastname: Trarbach
authors.forename: M
authors.initials: M
authors.lastname: Moehler
authors.forename: V
authors.initials: V
authors.lastname: Heinemann
authors.forename: C-H
authors.initials: CH
authors.lastname: Köhne
authors.forename: M
authors.initials: M
authors.lastname: Przyborek
authors.forename: C
authors.initials: C
authors.lastname: Schulz
authors.forename: V
authors.initials: V
authors.lastname: Sneller
authors.forename: G
authors.initials: G
authors.lastname: Gallant
authors.forename: S
authors.initials: S
authors.lastname: Kanzler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C507357:mapatumumab