This competing renewal proposes to define the recommended phase II dose and toxicities of new antineoplastic agents, including approaches to amelioration of such toxicity;to define the pharmacokinetics, pharmacodynamics, and pharmacogenetics of new antineoplastic agents;to develop new combinations that enhance the therapeutic index and/or oral bioavailability of new or established agents;and to develop and implement novel methodological approaches to phase I studies. This application includes four ongoing studies: 1) XK469 as a single dose every 3 weeks, 2) cilengitide by prolonged continuous infusion, 3) PXD101 and 5-azacitidine in leukemia, and 4) a randomized dose-escalation study of sorafenib using 12- hour ambulatory blood pressure monitoring as a biomarker. These studies build on the applicants'prior experience with these and related drugs. New studies will be proposed, as based upon the availability of new agents (in response to NCI requests for Letters of Intent). In addition, unsolicited Letters of Intent will be submitted, as determined by the scientific interests of the applicants. Particular areas of expertise and interest include pharmacogenetics and noninvasive biomarkers (such as ambulatory blood pressure monitoring or serum measurements of tyrosine kinase receptors). Most of the studies will evaluate novel therapies in patients with advanced solid tumors. In addition, the applicants anticipate maintaining at least one ongoing study for patients with advanced hematologic malignancies, and at least one study that is open to older children (minimum age 14 years or weight of 45 kg or more). All of the proposed studies will include pharmacokinetic or correlative components. The latter will include pharmacodynamic studies of tumor and normal tissue evaluating signal transduction endpoints, as well as pharmacogenetic studies. The proposed pharmacogenetic studies will be performed in collaboration with the Pharmacogenetics of Anticancer Agents Research (PAAR) Group, chaired by the Principal Investigator. The PAAR Group is part of a larger NIH Pharmacogenetics Research Network, administered through NIGMS. The applicants will also participate in the Investigational Drug Steering Committee and its Task Forces.
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