Kummar Shivaani, Gutierrez Martin, Gardner Erin R, Donovan Erin, Hwang Kyunghwa, Chung Eun Joo, Lee Min-Jung, Maynard Kim, Kalnitskiy Mikhail, Chen Alice, Melillo Giovanni, Ryan Qin C, Conley Barbara, Figg William D, Trepel Jane B, Zwiebel James, Doroshow James H, Murgo Anthony J
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5411-7. doi: 10.1158/1078-0432.CCR-07-0791.
MS-275 is a histone deacetylase inhibitor that has shown potent and unique anticancer activity in preclinical models. The aims of this phase I trial were to determine the dose-limiting toxicities and maximum tolerated dose of oral MS-275 in humans administered with food on a once weekly schedule and to study the pharmacokinetics of oral MS-275.
Patients with refractory solid tumors and lymphoid malignancies were treated with oral MS-275 on a once weekly schedule for 4 weeks of a 6-week cycle. Samples for pharmacokinetic and pharmacodynamic analyses were collected during cycle 1. Protein acetylation in subpopulations of peripheral blood mononuclear cells was measured using a multivariable flow cytometry assay.
A total of 22 patients were enrolled, and 19 were considered evaluable for toxicity. The maximum tolerated dose was 6 mg/m(2). No National Cancer Institute Common Toxicity Criteria grade 4 toxicities were observed. Dose-limiting grade 3 toxicities were reversible and consisted of hypophosphatemia, hyponatremia, and hypoalbuminemia. Non-dose-limiting grade 3 myelosuppression was also observed. The mean terminal half-life of MS-275 was 33.9 +/- 26.2 and the T(max) ranged from 0.5 to 24 h. Although there was considerable interpatient variability in pharmacokinetics, the area under the plasma concentration versus time curve increased linearly with dose.
MS-275 is well tolerated at a dose of 6 mg/m(2) administered weekly with food for 4 weeks every 6 weeks. Drug exposure increases linearly with dose, and protein acetylation increased in all the subpopulations of peripheral blood mononuclear cells following MS-275 administration.
MS-275是一种组蛋白去乙酰化酶抑制剂，在临床前模型中已显示出强大且独特的抗癌活性。本I期试验的目的是确定每周一次随食物服用的口服MS-275在人体中的剂量限制性毒性和最大耐受剂量，并研究口服MS-275的药代动力学。
难治性实体瘤和淋巴恶性肿瘤患者接受口服MS-275治疗，每周一次，为期6周的周期中的4周。在第1周期收集药代动力学和药效学分析样本。使用多变量流式细胞术测定法测量外周血单个核细胞亚群中的蛋白质乙酰化。
共入组22例患者，其中19例被认为可进行毒性评估。最大耐受剂量为6mg/m²。未观察到美国国立癌症研究所常见毒性标准4级毒性。剂量限制性3级毒性是可逆的，包括低磷血症、低钠血症和低白蛋白血症。还观察到非剂量限制性3级骨髓抑制。MS-275的平均终末半衰期为33.9±26.2，Tmax范围为0.5至24小时。尽管患者间药代动力学存在相当大的变异性，但血浆浓度-时间曲线下面积随剂量呈线性增加。
MS-275在每6周一次、每周一次随食物服用4周、剂量为6mg/m²时耐受性良好。药物暴露随剂量线性增加，服用MS-275后外周血单个核细胞的所有亚群中蛋白质乙酰化均增加。
