title: A multicenter phase 1 study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody targeting αv integrins, in progressive castration-resistant prostate cancer with bone metastases after chemotherapy.
abstract: BACKGROUND
  EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis.
  
  
  OBJECTIVE
  Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments.
  
  
  METHODS
  A phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥ 18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values.
  
  
  METHODS
  Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500 mg every 2 wk).
  
  
  METHODS
  Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used.
  
  
  CONCLUSIONS
  Patients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥ 18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials.
  
  
  CONCLUSIONS
  No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500 mg every 3 wk were chosen.
  
  
  BACKGROUND
  NCT00958477 (EMR 62242-002).
authors.affiliation: Department of Urology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany. Electronic address: Manfred.Wirth@uniklinikum-dresden.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Department of Urology, RWTH Aachen University, Aachen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Heidenreich
authors.affiliation: Department of Urology, Technical University of Munich Klinikum Rechts der Isar, Munich, Germany.
authors.forename: Jürgen E
authors.initials: JE
authors.lastname: Gschwend
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gil
authors.affiliation: Department of Urology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zastrow
authors.affiliation: Department of Urology, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Laniado
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerloff
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zühlsdorf
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Mordenti
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uhl
authors.affiliation: Merck KGaA, Darmstadt, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Lannert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology; D006801:Humans; D039564:Integrin alphaV / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018805:Sepsis / Q000139:chemically induced; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039564:Integrin alphaV; C000592911:Abituzumab; D005723:gamma-Glutamyltransferase; D017430:Prostate-Specific Antigen
keywords: Castrate-resistant prostate cancer (CRPC); EMD 525797; αv-Integrin overexpression