医学
药代动力学
恶心
药理学
药效学
耐火材料(行星科学)
毒性
加药
呕吐
外周血单个核细胞
内科学
肿瘤科
胃肠病学
物理
化学
体外
天体生物学
生物化学
作者
Qin Ryan,Donna Headlee,Milin Acharya,Alex Sparreboom,Jane B. Trepel,Ziyang Ye,William D. Figg,Kyunghwa Hwang,Eun Joo Chung,Anthony J. Murgo,Giovanni Melillo,Yusri Elsayed,Manish Monga,Mikhail Kalnitskiy,James A. Zwiebel,Edward A. Sausville
标识
DOI:10.1200/jco.2005.02.188
摘要
The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275.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/m2 and the dose was escalated in three- to six-patient cohorts based on toxicity assessments.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/m2 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 > or = 3 months.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.
科研通智能强力驱动
Strongly Powered by AbleSci AI