This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary objectives of this multicenter phase I trial are to determine the maximum tolerated dose, to obtain pharmacokinetic studies, to describe treatment-related and dose-limiting toxicities, and to describe the anti-leukemia activity of SB-715992 given as an infusion in patients with acute leukemia. SB-715992 is a polycyclic, nitrogen-containing heterocycle also possessing amide and amine functions that acts by inhibiting a novel molecular target for anticancer therapy, the mitotic kinesin spindle protein (KSP) (also called HsEg5). SB-715992 is a potent inhibitor of cell growth, and causes cells to arrest in mitosis with unseparated centrosomes and monopolar mitotic spindles following both in vitro and in vivo treatment. SB-715992 demonstrates efficacy, complete response (CR) and partial responses (PR) on an intermittent schedule in a spectrum of preclinical tumor models, including models considered chemo-refractory. In two ongoing phase I studies of SB-715992 in patients with solid tumors, the drug has been well tolerated. This study will enroll patients 18 years and older with relapsed acute leukemia and patients with de novo acute leukemia who are not candidates for standard aggressive induction regimens due to advanced age or serious comorbid medical conditions. The study will utilize an accelerated titration design as outlined in the protocol. Escalated doses will be given intravenously over one hour for 3 consecutive days, every 21 days for a maximum of 3 cycles. Serum samples for pharmacokinetic studies will be obtained. Correlative laboratory studies will include evaluation of pretreatment bone marrow aspirates for expression of Beta-tubulin and KSP. Peripheral mononuclear cells and bone marrow aspirates for studies of cytoskeleton morphology and in situ apoptosis during treatment. Results of investigational laboratory studies will be correlated with clinical response. Patients who achieve a complete or partial response or stable disease will be eligible to receive up to 4 additional consolidation courses of treatment every 3 weeks or until bone marrow aplasia is achieved (defined as bone marrow cellularity less than or equal to 5% and/or less than or equal to 5% marrow blasts). The study will enroll a total of 30 subjects at all sites. 15 subjects are expected at this site.
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