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Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
ABT-510: Mimicking the behavior of a natural antiangiogenic protein, thrombospondin-1, ABT-510 is being evaluated to determine its potential to block multiple proangiogenic growth factors including VEGF, bFGF, and interleukin-8. ABT-510 currently is being studied in phase-II clinical trials in various cancers including sarcoma, lymphoma, and kidney cancer. ABT-510 was granted an orphan drug designation by the FDA for soft tissue sarcoma. A phase-I study of ABT-510 was conducted in which ABT-510 was administered subcutaneously as a continuous infusion (100 mg/24 hour) and bolus injections (100, 200, and 260 mg QD) in 28-day cycles. Thirty-nine patients received a total of 144 treatment cycles. Administration by continuous infusion was hampered by the onset of painful skin infiltrates at the injection site. In the bolus injection regimens, the most common toxicities observed were mild injection-site reactions and fatigue. MTD was not defined, but 260 mg was defined as the maximum clinically practical dose. Median serum bFGF levels decreased from 14.1 pg/mL (range, 0.5–77.7 pg/mL) at baseline to 3.2 pg/mL (range, 0.2–29.4 pg/mL) after 56 days of treatment (P = 0.003). No correlations with time on study or ABT-510 dose or exposure were observed for individual changes in bFGF. SD lasting for six cycles or more was seen in six patients. ABT-510 demonstrated a favorable toxicity profile and linear and time-independent PKs with biologically relevant plasma concentrations (plasma concentrations > 100 ng/mL > 3 hr/day). The significant number of patients with prolonged SD and the convenient method of dosing merit further studies with this angiogenesis inhibitor (81). Phase-II studies in NSCLC are planned.
The evolving role of antiangiogenic therapies in glioblastoma multiforme: current clinical significance and future potential
Published in Expert Opinion on Investigational Drugs, 2019
Casey Anthony, Nikol Mladkova-Suchy, David Cory Adamson
ABT 510, nonapeptide thrombospondin 1 (TSP1), is a mimetic that promotes its antiangiogenic effect through the CD36 molecule, mimicking the natural effect of TSP1. It has been evaluated in a phase I study involving 23 patients with newly diagnosed GBM who received the drug in combination with TMZ and radiation [37]. Although preclinical data were quite promising, showing significant inhibition of mice glioma xenografts [38], addition of the drug to the standard treatment lead only to a slight improvement in median OS to 14.8 months. Nonetheless, given that the toxicity of the drug was low compared to other molecular targeting agents, future combination studies may provide further insight into the benefit of this drug for GBM patients.