title: Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5).
abstract: BACKGROUND
  TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8.
  
  
  METHODS
  A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly.
  
  
  RESULTS
  Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days.
  
  
  CONCLUSIONS
  Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.
authors.affiliation: University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, Alabama 35294-3300, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Jatin
authors.initials: J
authors.lastname: Shah
authors.forename: Tina
authors.initials: T
authors.lastname: Wood
authors.forename: James
authors.initials: J
authors.lastname: Posey
authors.forename: Ronda
authors.initials: R
authors.lastname: Carlisle
authors.forename: Catherine
authors.initials: C
authors.lastname: Copigneaux
authors.forename: Feng Roger
authors.initials: FR
authors.lastname: Luo
authors.forename: Slawomir
authors.initials: S
authors.lastname: Wojtowicz-Praga
authors.forename: Ivor
authors.initials: I
authors.lastname: Percent
authors.forename: Mansoor
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C552861:tigatuzumab