Protocol Number: 09-C-0119
-The rate limiting step in the synthesis of guanine nucleotides is catalyzed by the enzyme inosine monophosphate dehydrogenase (IMPDH) and so inhibition of this enzyme will result in depletion of guanine nucleotide pools, cessation of DNA synthesis, cell cycle block at the Gr(1)/S interface and interference with cell division. -The reduction in guanine nucleotide pools interferes with the ability of G-coupled proteins to act as intracellular signal transducers. IMPDH inhibition -AVN944 is a small-molecule, uncompetitive inhibitor of cell proliferation -A Phase I study in patients with hematologic malignancies is active and accruing subjects. The maximum-tolerated dose (MTD) has not been reached and no pattern of organ-specific or dose-progressive toxicity has been observed. Objectives: Primary -The dose limiting toxicities with AVN944 in patients with advanced stage solid tumors -The MTD with AVN944 in patients with advanced stage solid tumors Secondary: -Pharmacokinetics and the pharmacodynamics of AVN944 by study cohort, -The extent of IMPDH inhibition on tumor tissue and peripheral blood mononuclear cells (PBMC) -The effect of AVN944 on tumors by measuring guanine nucleotide pools levels using PBMC's -The effect of AVN944 on tumors by analyzing expression of genes related to IMPDH Eligibility: -Inclusion: --Patients must have histologically confirmed malignancy --Patients must be at least 4 weeks since prior chemotherapy or radiation therapy and 2 weeks since prior hormonal therapy. --ECOG performance status less than or equal to 2 --Life expectancy of greater than 3 months --Age greater than or equal to 18 -Exclusion: --Patients with known active brain metastaseso r other CNS involvement --History of allergic reactions attributed to compounds of similar chemical or biologic --Prior treatment with an IMPDH-inhibitor --History of solid organ transplant and are on IMPDFI inhibitors therapy Design: -Phase I Trial using 3+3 trail design using starting cohort of 150 mg twice per day escalating to 750 mg twice per day -60 patients to be enrolled over 30-36 months -AVN944 will be administered in 28 day treatment cycles
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National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 05/05/2009
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