Evaluation of pharmacodynamic biomarkers in a Phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours.
BACKGROUND
Dulanermin (rhApo2L/TRAIL) induces apoptosis by binding to death receptors DR4 and DR5, leading to caspase activation and subsequent cell death. A Phase1a trial evaluated the safety and tolerability of dulanermin in patients with advanced tumours. One aim was to develop and validate pharmacodynamic biomarkers to monitor dulanermin activity in patient serum.


METHODS
We optimised assays to measure the cell-death markers caspase 3/7, cytokeratin 18 and genomic DNA in serum. Mice bearing Colo205 xenografts were treated with dulanermin and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored apoptotic markers in patients who received dulanermin.


RESULTS
We detected transient increases in apoptotic markers in mouse sera 8-24 h after dulanermin treatment. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumours. A statistically significant increase in serum caspase 3/7 was detected in cohorts of colorectal and sarcoma patients 24 h after receiving dulanermin dosed above 4 mg kg(-1).


CONCLUSIONS
Owing to limited responses in the Phase 1a study, the changes in circulating cell-death markers were not evaluable. Future studies with dulanermin are needed to determine the utility of these assays with respect to providing evidence of activity or predicting overall response.
Department of Molecular Sciences, Amgen Inc., 1201 Amgen Court West, Seattle, WA 98119, USA.
Y
Y
Pan
R
R
Xu
M
M
Peach
C-P
CP
Huang
D
D
Branstetter
W
W
Novotny
R S
RS
Herbst
S G
SG
Eckhardt
P M
PM
Holland
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000097:blood*; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D017931:DNA Primers; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human