Phase I trial to study the effectiveness of SB-715992 in treating patients who have acute leukemia, chronic myelogenous leukemia, or advanced myelodysplastic syndromes. Drugs used in chemotherapy, such as SB-715992, work in different ways to stop cancer cells from dividing so they stop growing or die
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of SB-715992 given as a daily x 3 infusion in patients with acute leukemia. II. To obtain pharmacokinetic studies of SB-715992 given on a 3 consecutive day schedule every 3 weeks. III. To describe treatment-related and dose-limiting toxicities of SB-715992 in patients with acute leukemia. IV. To describe the anti-leukemia activity of SB-715992. V. To correlate treatment-related toxicities with pharmacokinetic studies of SB-715992. SECONDARY OBJECTIVES: I. To validate KSP as the major target of SB-715992 by determining the impact of drug treatment on cytoskeletal morphology in peripheral blood mononuclear cells and circulating leukemic blasts. II. To determine the expression of tubulin isoforms and KSP in leukemic blasts and explore possible relationships between gene expression and response to SB-715992. OUTLINE: This is a dose-escalation, multicenter study. Induction chemotherapy: Patients receive SB-715992 IV over 1 hour on days 1-3. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Consolidation chemotherapy: Patients achieving complete response (CR), partial response (PR), or stable disease (SD) after induction chemotherapy receive up to 4 additional courses of SB-715992 beyond CR, PR, or SD. Cohorts of 3-6 patients receive SB-715992 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 9 patients are treated at the MTD. Patients are followed for 6 weeks. PROJECTED ACCRUAL: Approximately 15-30 patients will be accrued for this study within 7.5-15 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Case Western Reserve University
Cleveland, Ohio, United States
Maximum tolerated dose (MTD) of ispinesib, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0
Time frame: Up to day 28
Pharmacokinetics of ispinesib in terms of total systemic clearance, peak concentration, area under the curve (AUC), and half-lives
Summarized with histograms, medians, quartiles and ranges. Scatterplots and correlation coefficients will be used to evaluate the association between the pharmacokinetic (PK) variables and the ispinesib dose, as well the changes in the peripheral blood mononuclear cell (PBMC) values.
Time frame: Up to 96 hours post-infusion
Treatment-related and dose-limiting toxicities of ispinesib, based on the NCI CTCAE v3.0
Time frame: Up to 2 years
Clearing of circulating peripheral blasts
Time frame: By 35 days from start of most recent course of chemotherapy
Attainment of aplastic bone marrow
Scatterplots, means, standard deviations, and confidence intervals will be constructed to compare responders and non-responders.
Time frame: By 35 days from start of most recent course of chemotherapy
Achievement of complete or partial remission
Scatterplots, means, standard deviations, and confidence intervals will be constructed to compare responders and non-responders.
Time frame: By 35 days from start of most recent course of chemotherapy
Correlation between treatment-related toxicities with pharmacokinetic studies
Scatterplots, means, standard deviations, and confidence intervals will be constructed to compare responders and non-responders.
Time frame: By 35 days from start of most recent course of chemotherapy
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