title: A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases.
abstract: OBJECTIVE
  This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases.
  
  
  METHODS
  Patients with p-Met (phosphorylated c-Met)-positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed.
  
  
  RESULTS
  No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (-53%), p-ERK (-43%), p-Akt (-2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4-10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year.
  
  
  CONCLUSIONS
  Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle.
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York jtabernero@vhio.net.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Elez
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Herranz
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rico
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prudkin
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jordi
authors.initials: J
authors.lastname: Andreu
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Mateos
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Maria Josep
authors.initials: MJ
authors.lastname: Carreras
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: May
authors.initials: M
authors.lastname: Han
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: James
authors.initials: J
authors.lastname: Gifford
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Credi
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Shefali
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Philip
authors.initials: P
authors.lastname: Komarnitsky
authors.affiliation: Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001247:Asthenia / Q000139:chemically induced; D003371:Cough / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004487:Edema / Q000139:chemically induced; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D008107:Liver Diseases / Q000209:etiology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010146:Pain / Q000139:chemically induced; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D017228:Hepatocyte Growth Factor; C583360:ficlatuzumab; D019859:Proto-Oncogene Proteins c-met