title: Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study.
abstract: BACKGROUND
  Results of preclinical studies have shown that EGFR immunoliposomes have substantial antitumour effects. We aimed to assess the tolerability, safety, pharmokinetics, and efficacy of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in patients with solid tumours.
  
  
  METHODS
  In this first-in-man, open-label, phase 1 clinical study, we enrolled patients at University Hospital of Basel, Switzerland, who had EGFR-overexpressing advanced solid tumours no longer amenable to standard treatment. Anti-EGFR ILs-dox nanoparticles were constructed by covalently linking pegylated liposomes containing doxorubicin to antigen-binding fragments (Fab') of cetuximab. We intravenously infused the nanoparticle at escalating doses (doxorubicin 5 mg/m(2), 10 mg/m(2), 20 mg/m(2), 30 mg/m(2), 40 mg/m(2), 50 mg/m(2), and 60 mg/m(2)) once every 4 weeks for a maximum of six cycles. The primary endpoint was to establish the maximum tolerated dose. We analysed patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01702129.
  
  
  RESULTS
  Between Jan 30, 2007, and March 4, 2010, we gave the drug to 29 patients, three of whom were withdrawn from the study because we could not complete a safety assessment. Of the 26 patients assessed for the primary endpoint, two who received a dose of 60 mg/m(2) had dose-limiting toxicities (one had neutropenia and the other had anaemia); therefore, the maximum tolerated dose was defined as 50 mg/m(2). At all lower doses, anti-EGFR ILs-dox was well tolerated; grade 1 skin toxicity occurred in two patients only. We recorded 22 serious adverse events (SAEs) in 17 patients, mostly due to tumour progression. Three SAEs were fatal. Only three SAEs (febrile neutropenia, septicaemia, and a fatal massive oral bleed) were probably or possibly related to study drug. No patients had palmar-plantar erythrodysaesthesia, alopecia, cardiotoxicity, or cumulative toxicity. Best response to treatment included one complete response, one partial response, and ten stable disease lasting 2-12 months (median 5·75 months).
  
  
  CONCLUSIONS
  Because anti-EGFR ILs-dox was well tolerated up to 50 mg doxorubicin per m(2), and we recorded clinical activity, further assessment of this nanoparticle at this dose in phase 2 trials is warranted.
  
  
  BACKGROUND
  Cancer League Basel, Swiss Cancer League, Schoenmakers-Müller Foundation, and Werner Geissberger Foundation.
authors.affiliation: Division of Oncology, University Hospital of Basel, Basel, Switzerland. christoph.mamot@ksa.ch
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.forename: Reto
authors.initials: R
authors.lastname: Ritschard
authors.forename: Andreas
authors.initials: A
authors.lastname: Wicki
authors.forename: Gregor
authors.initials: G
authors.lastname: Stehle
authors.forename: Thomas
authors.initials: T
authors.lastname: Dieterle
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Christoph
authors.initials: C
authors.lastname: Hilker
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deuster
authors.forename: Richard
authors.initials: R
authors.lastname: Herrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D058726:Nanoconjugates; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D058726:Nanoconjugates; D004317:Doxorubicin; D066246:ErbB Receptors; D000068818:Cetuximab