A Phase I Study of ABT-510 in Combination With Bevacizumab in Advanced Solid
ABT-510: In the early 1990s, thrombospondin (TSP-1) was first recognized as an endogenously
produced inhibitor of angiogenesis. Since then, thrombospondin has been shown to inhibit
neovascularization and tumorigenesis in numerous mouse models. Its anti- angiogenesis
properties have been localized to its N-terminal region. Although smaller fragments of this
region retain some of thrombospondin's anti-angiogenesis properties, researchers have
discovered that specific amino acid substitutions can greatly enhance these properties. From
these efforts, ABT-510, a nine-amino acid synthetic peptide has emerged as a novel
anti-angiogenesis agent. The peptide is soluble and stable in water and is administered
parenterally as an acetate salt in 5% dextrose solution for clinical use.
ABT-510 has been evaluated in three Phase I studies: one single-dose study in healthy
volunteers and two studies in cancer patients. Doses ranging from 10 mg to 260 mg have been
evaluated as IV infusions (30-minute), subcutaneous bolus injections, or 24-hour
subcutaneous infusions. Overall, ABT-510 has been well tolerated. A preliminary review of
the 103 case report forms collected to date identified a total of 1306 adverse events.
Ninety-one percent (1195/1306) of these events were considered to be mild or moderate in
nature. Eighty-one percent (1052/1306) of these events were reported as not related to or
probably not related to ABT-510. The most common adverse events, occurring in >10% of the
patients, include injection site reaction, asthenia, abdominal pain, nausea, anorexia, pain,
headache, vomiting, diarrhea, dyspnea, constipation, cough increased, back pain, peripheral
edema, dizziness, insomnia, anemia, fever, sweating, chest pain, and rash.
Bevacizumab (Avastin) is a recombinant, humanized, monoclonal antibody directed against
vascular endothelial growth factor (VEGF). This antibody blocks binding of the ligand VEGF
with its receptor. VEGF is known to play a pivotal role in tumor angiogenesis and is a
significant mitogenic stimulus for arterial, venous, and lymphatic endothelial cells. It can
induce vascular permeability essential for extracellular remodeling and can serve as an
endothelial cell survival factor. Phase III studies in 1st line colorectal cancer, 2nd line
colorectal cancer, 1st line breast cancer, and 1st line non-small cell lung cancer have all
demonstrated clinical benefit in terms of overall survival, progression free survival, and
tumor response [Refs.. HH NEJM, A Sandler ASCO2005, L Miller ASCO 2005]. Efficacy has also
been noted in phase II studies of renal cell, ovarian, glioma, and other tumor types. Side
effects of bevacizumab include approximately 10-20% rate of hypertension requiring
anti-hypertensives, uncommon aterial thromboembolilc events (myocardial infarction,
unstable angina, cerebrovascular events, transient ischemic attacks, etc) with background
rates increased from approximately 1-2% to 2-4%, and an approximately 1-2% risk of GI
perforation.
Aside from this pivotal phase III colorectal cancer study, the dose of bevacizumab used for
all other clinical trials has been 10mg/kg biweekly. A dose of bevacizumab at 10 mg/kg will
be used in this study because it is consistent with the dosing used in most ongoing and
planned bevacizumab studies and it has been shown, when compared to lower doses, to have
comparable or improved activity.
Based on available data, it is a reasonable hypothesis that the combination of ABT-510 and
bevacizumab will be a safe and potentially efficacious anti-angiogenesis strategy for the
treatment of adult solid tumors. This combination may have utility directly or may prove
useful when subsequently combined with other anti-angiogenic agents or standard chemotherapy
regimens. An important aspect of this proposed study will be the inclusion of a clinical
dermal wound angiogenesis assay which will help quantify and characterize the
anti-angiogenic contribution of each agent in this combination. Therefore, this study is
meant to provide important safety information on this combination, but also insight into the
additive mechanistic effects of two agents with different mechanisms of action.
Interventional
Intervention Model: Single Group Assignment, Masking: Open Label
To determine the recommended Phase II dose for the combination of ABT-510 plus bevacizumab
Each Cycle (28-days)
Yes
Herb Hurwitz, MD
Principal Investigator
Duke University
United States: Food and Drug Administration
Pro00008797
NCT00586092
September 2005
February 2013
Name | Location |
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Duke University Medical Center | Durham, North Carolina 27710 |