title: A first-in-human study of the anti-α5β1 integrin monoclonal antibody PF-04605412 administered intravenously to patients with advanced solid tumors.
abstract: OBJECTIVE
  A first-in-human clinical trial of a fully human, Fc-engineered IgG1 monoclonal antibody targeting integrin α5β1 was conducted to evaluate tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity.
  
  
  METHODS
  Escalating doses of PF-04605412 were given IV on day 1, 28 and every 2 weeks thereafter to patients with advanced solid tumors until disease progression or unacceptable toxicity. Sequential dose cohorts were evaluated based on a modified 3 + 3 dose-escalation design. The starting dose was 7.5 mg based on preclinical data.
  
  
  RESULTS
  Thirty-three patients were enrolled to six dose levels (7.5, 11.25, 16.9, 34, 68 and 136 mg). Twenty-three patients were evaluable for the primary endpoint (determination of the maximum tolerated dose). Five patients required permanent drug discontinuation due to acute infusion-related reactions, which occurred as grade 3 events in two patients. PK analysis indicated that the targeted drug exposure based on preclinical models was not achieved by the tolerated doses and PK modeling suggesting that doses at least fivefold higher would be necessary. No anti-tumor activity was observed.
  
  
  CONCLUSIONS
  Based on the safety data, the risks associated with the likelihood of significant cytokine-mediated infusion reactions at higher doses, the projected high dose necessary to affect on the biological target and the lack of anti-tumor activity at the doses explored, the trial was prematurely terminated without determining a formal maximum tolerated dose. Further clinical development of PF-04605412 has been discontinued.
authors.affiliation: The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mateo
authors.forename: J
authors.initials: J
authors.lastname: Berlin
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.forename: R B
authors.initials: RB
authors.lastname: Cohen
authors.forename: V
authors.initials: V
authors.lastname: Keedy
authors.forename: G
authors.initials: G
authors.lastname: Mugundu
authors.forename: Lianglin
authors.initials: L
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Abbattista
authors.forename: C
authors.initials: C
authors.lastname: Davis
authors.forename: C
authors.initials: C
authors.lastname: Gallo Stampino
authors.forename: H
authors.initials: H
authors.lastname: Borghaei
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005483:Flushing / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D039081:Integrin alpha5beta1 / Q000276:immunology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D039081:Integrin alpha5beta1; C000594806:PF-04605412