title: Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors.
abstract: OBJECTIVE
  The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)-neutralizing monoclonal antibody, in patients with solid tumors.
  
  
  METHODS
  Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti-AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed.
  
  
  RESULTS
  AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti-AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses.
  
  
  CONCLUSIONS
  AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents.
authors.affiliation: Premiere Oncology of Arizona, Scottsdale, Arizona 85258, USA. mgordon@premiereoncology.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Sweeney
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Abraham
authors.initials: A
authors.lastname: Anderson
authors.forename: Darrin M
authors.initials: DM
authors.lastname: Beaupre
authors.forename: Daniel
authors.initials: D
authors.lastname: Branstetter
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Burgess
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.forename: Paula
authors.initials: P
authors.lastname: Kaplan-Lefko
authors.forename: Ian M
authors.initials: IM
authors.lastname: Leitch
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.forename: Lucy
authors.initials: L
authors.lastname: Yan
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000276:immunology; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C524459:rilotumumab; D017228:Hepatocyte Growth Factor