R. Klisovic, G. Tricot, S. Coutre
Jun 20, 2007
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Journal
Journal of Clinical Oncology
Abstract
14026 Background: AVN-944 is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme that catalyzes the rate- limiting step in guanine nucleotide synthesis, and induces apoptosis in malignant hematopoietic cell lines in vitro. Methods: This phase I study employed open-label dose escalations in patients (pts) with relapsed, refractory hematologic cancers with safety, pharmacokinetic (PK), pharmacodynamic, & efficacy endpoints. Between 12/05 and 1/07 a total of 70 cycles of AVN944 at 25 (7pts), 50 (6pts), 75 (7pts), 100 (7pts) or 125 mg (3pts) b.i.d. orally X 21d every 28d were administered to 30 pts with AML (12), ALL (2), CLL (3), and multiple myeloma (13). Peripheral blood mononuclear cell (PBMC) or leukemic blast samples were obtained from all pts pre and post-receiving AVN944 to determine effects on GTP pools, IMPDH activity, and to correlate these changes to response in a 32-gene set that relates directly to cellular pathways dependent upon guanine nucleotide biosynthesis. Results: Phar...