PMID- 20458040
OWN - NLM
STAT- MEDLINE
DCOM- 20100908
LR  - 20220331
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 28
IP  - 17
DP  - 2010 Jun 10
TI  - Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual 
      proapoptotic receptor agonist, in patients with advanced cancer.
PG  - 2839-46
LID - 10.1200/JCO.2009.25.1991 [doi]
AB  - PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
FAU - Herbst, Roy S
AU  - Herbst RS
AD  - 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
FAU - Eckhardt, S Gail
AU  - Eckhardt SG
FAU - Kurzrock, Razelle
AU  - Kurzrock R
FAU - Ebbinghaus, Scot
AU  - Ebbinghaus S
FAU - O'Dwyer, Peter J
AU  - O'Dwyer PJ
FAU - Gordon, Michael S
AU  - Gordon MS
FAU - Novotny, William
AU  - Novotny W
FAU - Goldwasser, Meredith A
AU  - Goldwasser MA
FAU - Tohnya, Tanyifor M
AU  - Tohnya TM
FAU - Lum, Bert L
AU  - Lum BL
FAU - Ashkenazi, Avi
AU  - Ashkenazi A
FAU - Jubb, Adrian M
AU  - Jubb AM
FAU - Mendelson, David S
AU  - Mendelson DS
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100510
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Agents/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Apoptosis/*drug effects
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasms/blood/*drug therapy/pathology
MH  - Recombinant Proteins/administration & dosage/adverse effects/pharmacokinetics
MH  - TNF-Related Apoptosis-Inducing Ligand/*administration & dosage/adverse 
      effects/pharmacokinetics
EDAT- 2010/05/12 06:00
MHDA- 2010/09/09 06:00
CRDT- 2010/05/12 06:00
PHST- 2010/05/12 06:00 [entrez]
PHST- 2010/05/12 06:00 [pubmed]
PHST- 2010/09/09 06:00 [medline]
AID - JCO.2009.25.1991 [pii]
AID - 10.1200/JCO.2009.25.1991 [doi]
PST - ppublish
SO  - J Clin Oncol. 2010 Jun 10;28(17):2839-46. doi: 10.1200/JCO.2009.25.1991. Epub 
      2010 May 10.