title: A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors.
abstract: OBJECTIVE
  To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.
  
  
  METHODS
  This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.
  
  
  RESULTS
  Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a >20% decrease in volume transfer constant (K(trans)), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.
  
  
  CONCLUSIONS
  AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574-84. ©2016 AACR.
authors.affiliation: Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland, Ohio. afshin.dowlati@uhhospitals.org.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahovic
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Natale
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Erik
authors.initials: E
authors.lastname: Rasmussen
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Indrajeet
authors.initials: I
authors.lastname: Singh
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: John
authors.initials: J
authors.lastname: Rossi
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Gregory
authors.initials: G
authors.lastname: Friberg
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Pickett
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000970:Antineoplastic Agents