A Phase I Study of ABT-510 in Combination With Bevacizumab in Advanced Solid Tumors
The primary objective of this study is to determine the recommended Phase II dose for the combination of ABT-510 plus bevacizumab in patients with advanced solid tumors and to evaluate dose limiting toxicities and non-dose limiting toxicities of this combination. The secondary objectives are to collect preliminary data on the effect of the combination of ABT-510 plus bevacizumab versus each agent individually on dermal wound angiogenesis in a skin biopsy and to collect preliminary data on the clinical activity of this combination (tumor response rate, progression-free survival, rate of stable disease > 6 months).
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||A Phase I Study of ABT-510 in Combination With Bevacizumab in Advanced Solid|
- To determine the recommended Phase II dose for the combination of ABT-510 plus bevacizumab [ Time Frame: Each Cycle (28-days) ] [ Designated as safety issue: Yes ]
- To collect preliminary data on the clinical activity of this combination (tumor response rate, progression-free survival, rate of stable disease > 6 months). [ Time Frame: Each Cycle (28-days) ] [ Designated as safety issue: No ]
|Study Start Date:||September 2005|
|Study Completion Date:||February 2013|
|Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
This trial employs a phase I design with a dose escalation stage (stage I) and an expansion stage (stage 2) to better describe the tolerability of this combination and the effect of this combination on several biomarkers. In this second stage there will be two groups, each with ten patients, to better describe the tolerability of the bevacizumab/ABT-510 combination and the effect of this combination on several biomarkers. The primary objective of this study is to estimate the MTD/recommended phase II dose regimen. All other objectives are exploratory in nature.
Drug: bevacizumab, ABT-510
Other Name: avastin
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.
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|Principal Investigator:||Herb Hurwitz, MD||Duke University|