title: Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer.
abstract: OBJECTIVE
  Apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL)-a member of the tumor necrosis factor cytokine family-induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.
  
  
  METHODS
  This phase I, open-label, dose-escalation study treated patients with advanced cancer with rhApo2L/TRAIL doses ranging from 0.5 to 30 mg/kg/d, with parallel dose escalation for patients without liver metastases and with normal liver function (cohort 1) and for patients with liver metastases and normal or mildly abnormal liver function (cohort 2). Doses were given daily for 5 days, with cycles repeating every 3 weeks. Assessments included adverse events (AEs), laboratory tests, pharmacokinetics, and imaging to evaluate antitumor activity.
  
  
  RESULTS
  Seventy-one patients received a mean of 18.3 doses; seven patients completed all eight treatment cycles. The AE profile of rhApo2L/TRAIL was similar in cohorts 1 and 2. The most common AEs were fatigue (38%), nausea (28%), vomiting (23%), fever (23%), anemia (18%), and constipation (18%). Liver enzyme elevations were concurrent with progressive metastatic liver disease. Two patients with sarcoma (synovial and undifferentiated) experienced serious AEs associated with rapid tumor necrosis. Two patients with chondrosarcoma experienced durable partial responses to rhApo2L/TRAIL.
  
  
  CONCLUSIONS
  At the tested schedule and dose range, rhApo2L/TRAIL was safe and well tolerated. Dose escalation achieved peak rhApo2L/TRAIL serum concentrations equivalent to those associated with preclinical antitumor efficacy.
authors.affiliation: University of Texas M D Anderson Cancer Center, Thoracic Head and Neck Medicine Clinic, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030, USA. rherbst@mdanderson.org
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Scot
authors.initials: S
authors.lastname: Ebbinghaus
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.forename: William
authors.initials: W
authors.lastname: Novotny
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Goldwasser
authors.forename: Tanyifor M
authors.initials: TM
authors.lastname: Tohnya
authors.forename: Bert L
authors.initials: BL
authors.lastname: Lum
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human