title: Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study.
abstract: OBJECTIVE
  To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of mapatumumab, a fully human monoclonal antibody targeting tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with gemcitabine and cisplatin.
  
  
  METHODS
  Patients with advanced solid tumors received gemcitabine 1,250 mg/m(2) i.v. on days 1 and 8 and cisplatin 80 mg/m(2) i.v. on day 1 of each 21-day cycle. Escalating mapatumumab doses were administered i.v. every 21 days. Toxicity was evaluated and pharmacokinetic analysis of plasma mapatumumab, gemcitabine, 2-difluoro-2-deoxyuridine, and unbound and total platinum was done. TRAIL-R1 tumor expression was determined immunohistochemically.
  
  
  RESULTS
  Forty-nine patients received mapatumumab (1 mg/kg, n = 4; 3 mg/kg, n = 7; 10 mg/kg, n = 12; 20 mg/kg, n = 13; or 30 mg/kg, n = 13). A median of six cycles (range, 1-48) was administered. The adverse events most commonly observed reflect the toxicity profile of gemcitabine and cisplatin. Dose-limiting toxicities were seen in 3 of 12 patients at 10 mg/kg, consisting of grade 3 transaminitis, neutropenic fever, and grade 4 thrombocytopenia. At 20 mg/kg, 2 of 12 patients had dose-limiting toxicities, including grade 4 thrombocytopenia and grade 4 fatigue. The maximum tolerated dose was not reached. Pharmacokinetic interactions have not been observed. Twelve patients had a partial response, and 25 patients showed stable disease with a median duration of 6 months.
  
  
  CONCLUSIONS
  Mapatumumab in combination with gemcitabine and cisplatin is safe and well tolerated at doses up to 30 mg/kg. Further studies on this combination are warranted.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Constantijne H
authors.initials: CH
authors.lastname: Mom
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Corina N A M
authors.initials: CN
authors.lastname: Oldenhuis
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
authors.forename: Norma Lynn
authors.initials: NL
authors.lastname: Fox
authors.forename: Renée
authors.initials: R
authors.lastname: Miceli
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; D003841:Deoxycytidine; D002945:Cisplatin; C507357:mapatumumab; D000093542:Gemcitabine