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. OBJECTIVES: BMS 247550 is a cytotoxic agent that promotes and stabilizes the assembly of tubulin into microtubules, a process necessary for mitosis. It is an epothilone, a new class of non-taxane tubulin polymerization agents, which have demonstrated potent cytotoxic activity, working in much the same way as the taxanes to effect mitotoxic arrest. Objectives of this study are: 1. To determine the MTD of BMS-247550 given IV on continuous weekly schedule and to recommend a dose for phase II trials. 2. To determine the qualitative and quantitative toxicities of BMS-247550 given on a continuous weekly schedule. 3. To characterize the pharmacokinetics of BMS-247550 given on a continuous weekly schedule. 4. To explore the pharmacodynamics of a continuous weekly schedule using an assay that measures the amount of endogenous tubulin in peripheral blood mononuclear cells that exists in the polymerized versus unpolymerized state. 5. To collect information about the antitumor effects of BMS-247550 in patients with advanced cancer. RESEARCH PLAN: Patients must have histologically confirmed diagnosis of any malignant solid tumor or lymphoma and both male and female patients of reproductive potential must use an approved contraceptive method during the study and for two months afterwards. METHODS: Patients will be given BMS-247550 as a continuous infusion over one hour weekly on a four week cycle at an initial dose of 1mg/m2/week. Dose will be escalated in cohorts of three patients over four levels: 100% if toxicity is Grade 1 or less, 50% if toxicity is Grade 2, 25-33% if toxicity is Grade 2 or greater but not dose-limiting, and 20% if DLT. Enrollment of about 15 patients is anticipated at the GCRC in the South Texas Veterans Health care System, Audie Murphy Division. CLINICAL
BMS-247550 is a semi-synthetic analog of the natural product epothilone B, specifically designed to overcome the metabolic instability of the natural product. BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at a low nanomolar concentration. After a short IV infusion the terminal half-life in mice, rats, and dogs was 3.1, 9.6 and 24 hours, respectively, with high systemic clearance. In rats peripheral neuropathy, bone marrow/lymphoid depression and gastrointestinal and testicular changes were prominent. Severe gastrointestinal toxicity and death occurred in all dogs at a dose of 100 mg/m2. A dose of 10 mg/m2 was associated with transient minimal leukopenia and/or thrombocytopenia in one male and one female dog.
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