title: Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors.
  
  
  METHODS
  AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined.
  
  
  RESULTS
  Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001).
  
  
  CONCLUSIONS
  In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.
authors.affiliation: Premiere Oncology, Santa Monica, CA, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Marilyn
authors.initials: M
authors.lastname: Mulay
authors.forename: Andy
authors.initials: A
authors.lastname: Van Vugt
authors.forename: Michelle
authors.initials: M
authors.lastname: Purdom
authors.forename: Chaan
authors.initials: C
authors.lastname: Ng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Silverman
authors.forename: Antonis
authors.initials: A
authors.lastname: Koutsoukos
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bass
authors.forename: Ren Y
authors.initials: RY
authors.lastname: Xu
authors.forename: Anthony
authors.initials: A
authors.lastname: Polverino
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Wiezorek
authors.forename: David D
authors.initials: DD
authors.lastname: Chang
authors.forename: Robert
authors.initials: R
authors.lastname: Benjamin
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D019540:Area Under Curve; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; C519562:imetelstat