Phase I trial of antiangiogenic agent SU6668 in Pt w solid tumors

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Description: (provided by applicant) Receptor protein tyrosine kinases including VEGFR, PDGFR, and FGFR are involved in both angiogenesis and cell proliferation (thus providing attractive targets for novel anticancer therapies). Numerous approaches have been employed to block these pathways, including antibodies and kinase inhibitors. SU6668 is a small organic molecule that potently inhibits protein tyrosine kinase activities. Preclinical studies have demonstrated that SU6668 has in vivo activity, but minimal toxicity, against human tumor xenografts in animals, making SU6668 a good candidate for treating human cancers. There exists tremendous potential for SU6668 to be used alone or in combination with existing cytotoxic chemotherapeutic drugs. To date, most of the studies with this molecule have been preclinical; however, one phase I study is underway. It is clear that Standard studies to identify a maximum tolerated dose and optimum biologic dose are not appropriate because of a lack of suitable surrogate endpoints to differentiate the precise biologic effects of SU6668. Our proposed phase I surrogate endpoint study will determine the optimal biological dose of SU6668 and further assess its toxicity. Parallel tissue correlation studies and pharmacokinetic analyses will determine if therapeutic levels of SU6668 can be achieved in each patient. This study will also look for initial evidence of biologic activity using a composite of surrogate endpoints through the collaboration of our multidisciplinary team. These studies will include ( 1) ex vivo assays of serum antiangiogenic activity , (2) tissue biopsies analyzed for microvessel density , endothelial cell proliferation and apoptosis, and (3) noninvasive radiologic studies including positron emission tomography scans for F18 and O15 in all patients and either dynamic flow computed tomography or functional magnetic resonance imaging as deemed most appropriate in each case. It is our expectation that this clinical study will be sufficiently aided by efforts of the co-investigators and will provide clinical material for all the projects of this U54 grant.