Phase I Dose-Escalation Study of Recombinant Human Apo2L/TRAIL, a Dual Proapoptotic Receptor Agonist, in Patients With Advanced Cancer
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.
Top-30
Journals
|
2
4
6
8
10
12
14
16
18
|
|
|
Cancers
18 publications, 4.7%
|
|
|
Molecular Cancer Therapeutics
12 publications, 3.13%
|
|
|
Oncotarget
8 publications, 2.09%
|
|
|
Cancer Letters
8 publications, 2.09%
|
|
|
Journal of Controlled Release
8 publications, 2.09%
|
|
|
Oncology Reports
7 publications, 1.83%
|
|
|
International Journal of Molecular Sciences
7 publications, 1.83%
|
|
|
Cell Death and Disease
6 publications, 1.57%
|
|
|
British Journal of Cancer
6 publications, 1.57%
|
|
|
PLoS ONE
5 publications, 1.31%
|
|
|
Advanced healthcare materials
5 publications, 1.31%
|
|
|
Cancer Biology and Therapy
5 publications, 1.31%
|
|
|
Investigational New Drugs
4 publications, 1.04%
|
|
|
Scientific Reports
4 publications, 1.04%
|
|
|
Biochemical and Biophysical Research Communications
4 publications, 1.04%
|
|
|
Critical Reviews in Oncology/Hematology
4 publications, 1.04%
|
|
|
Biomaterials
4 publications, 1.04%
|
|
|
Resistance to Targeted Anti-Cancer Therapeutics
4 publications, 1.04%
|
|
|
Proceedings of the National Academy of Sciences of the United States of America
4 publications, 1.04%
|
|
|
Current Opinion in Oncology
3 publications, 0.78%
|
|
|
Cell Death and Differentiation
3 publications, 0.78%
|
|
|
BMC Cancer
3 publications, 0.78%
|
|
|
Journal of Cellular Biochemistry
3 publications, 0.78%
|
|
|
Cancer Medicine
3 publications, 0.78%
|
|
|
International Journal of Cancer
3 publications, 0.78%
|
|
|
Advances in Experimental Medicine and Biology
3 publications, 0.78%
|
|
|
mAbs
3 publications, 0.78%
|
|
|
Clinical Cancer Research
3 publications, 0.78%
|
|
|
eLife
3 publications, 0.78%
|
|
|
2
4
6
8
10
12
14
16
18
|
Publishers
|
10
20
30
40
50
60
70
80
90
|
|
|
Elsevier
87 publications, 22.72%
|
|
|
Springer Nature
73 publications, 19.06%
|
|
|
Wiley
34 publications, 8.88%
|
|
|
MDPI
31 publications, 8.09%
|
|
|
Taylor & Francis
22 publications, 5.74%
|
|
|
American Association for Cancer Research (AACR)
16 publications, 4.18%
|
|
|
Spandidos Publications
11 publications, 2.87%
|
|
|
American Chemical Society (ACS)
11 publications, 2.87%
|
|
|
Impact Journals
8 publications, 2.09%
|
|
|
Ovid Technologies (Wolters Kluwer Health)
8 publications, 2.09%
|
|
|
Frontiers Media S.A.
8 publications, 2.09%
|
|
|
Oxford University Press
8 publications, 2.09%
|
|
|
Royal Society of Chemistry (RSC)
6 publications, 1.57%
|
|
|
Public Library of Science (PLoS)
5 publications, 1.31%
|
|
|
Proceedings of the National Academy of Sciences (PNAS)
4 publications, 1.04%
|
|
|
SAGE
3 publications, 0.78%
|
|
|
Pleiades Publishing
3 publications, 0.78%
|
|
|
BMJ
3 publications, 0.78%
|
|
|
Hindawi Limited
3 publications, 0.78%
|
|
|
eLife Sciences Publications
3 publications, 0.78%
|
|
|
American Society of Clinical Oncology (ASCO)
3 publications, 0.78%
|
|
|
American Society for Clinical Investigation
2 publications, 0.52%
|
|
|
S. Karger AG
2 publications, 0.52%
|
|
|
Mary Ann Liebert
2 publications, 0.52%
|
|
|
American Association for the Advancement of Science (AAAS)
2 publications, 0.52%
|
|
|
Cold Spring Harbor Laboratory
2 publications, 0.52%
|
|
|
OAE Publishing Inc.
2 publications, 0.52%
|
|
|
The Endocrine Society
1 publication, 0.26%
|
|
|
Portland Press
1 publication, 0.26%
|
|
|
10
20
30
40
50
60
70
80
90
|
- We do not take into account publications without a DOI.
- Statistics recalculated weekly.