title: Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1.
abstract: OBJECTIVE
  To assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of mapatumumab (HGS-ETR1, TRM-1), a fully human agonist monoclonal antibody directed to the tumor necrosis factor-related apoptosis-inducing ligand receptor-1 (TRAIL-R1).
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of mapatumumab intravenously (IV) administered over 30 to 120 minutes, initially as a single dose and then repetitively. Plasma mapatumumab concentrations were measured and serum was assayed to detect human antimapatumumab antibody formation. Archival tumor specimens were collected to detect the presence of TRAIL-R1 by immunohistochemistry.
  
  
  RESULTS
  Forty-nine patients received 158 courses at doses ranging from 0.01 to 10 mg/kg IV. Initially, patients received mapatumumab as a single dose, then every 28 days repetitively, and then 10 mg/kg every 14 days. Mild (grade 1 or 2) fatigue, fever, and myalgia were the most frequently reported nonhematologic adverse events related to mapatumumab, whereas hematologic toxicity was not clinically significant. The mean (+/- standard deviation) clearance and terminal elimination half-life values for mapatumumab at 10 mg/kg every 14 days were 3.7 mL/d/kg (+/- 1.5 mL/d/kg) and 18.8 days (+/- 10.1 days), respectively. TRAIL-R1 was documented in 68% of patients' tumors assayed. Nineteen patients had stable disease, with two lasting 9 months.
  
  
  CONCLUSIONS
  Mapatumumab can be administered safely and feasibly at 10 mg/kg IV every 14 days. The absence of severe toxicities and the attainment of plasma mapatumumab concentrations that are active in preclinical models warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USAS. atolcher@idd.org
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Monica
authors.initials: M
authors.lastname: Mita
authors.forename: Neal J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Kristin
authors.initials: K
authors.lastname: Padavic
authors.forename: Monique
authors.initials: M
authors.lastname: Hill
authors.forename: Theresa
authors.initials: T
authors.lastname: Mays
authors.forename: Therese
authors.initials: T
authors.lastname: McCoy
authors.forename: Norma Lynn
authors.initials: NL
authors.lastname: Fox
authors.forename: Wendy
authors.initials: W
authors.lastname: Halpern
authors.forename: Alfred
authors.initials: A
authors.lastname: Corey
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C507357:mapatumumab