期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 23, 期 17, 页码 3912-3922出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2005.02.188
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Purpose The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase 11 dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275. Patients and Methods Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily X 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m(2) and the dose was escalated in three- to six-patient cohorts based on toxicity assessments. Results With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m(2) and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for >= 3 months. Conclusion The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly X 4, repeated every 6 weeks is presently being evaluated.
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