title: A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors.
abstract: BACKGROUND
  This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.
  
  
  METHODS
  Three to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208.
  
  
  RESULTS
  Fifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed.
  
  
  CONCLUSIONS
  In this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Tower Cancer Research Foundation, Beverly Hills, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosen
authors.affiliation: Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rabia
authors.initials: R
authors.lastname: Khan
authors.affiliation: Amgen Inc., Seattle, WA, USA.
authors.forename: Benny
authors.initials: B
authors.lastname: Amore
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Caudillo
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Loberg
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Gataree
authors.initials: G
authors.lastname: Ngarmchamnanrith
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Darrin M
authors.initials: DM
authors.lastname: Beaupre
authors.affiliation: Tower Cancer Research Foundation, Beverly Hills, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012074:Remission Induction; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: C000607903:AMG 208; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met
keywords: MET; first-in-human; prostate cancer; small molecule; solid tumors