A Phase I Pharmacokinetic and Pharmacodynamic Study of CHR-3996, an Oral Class I Selective Histone Deacetylase Inhibitor in Refractory Solid Tumors
A Phase I Pharmacokinetic and Pharmacodynamic Study of CHR-3996, an Oral Class I Selective Histone Deacetylase Inhibitor in Refractory Solid Tumors
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DOI：
10.1158/1078-0432.ccr-11-3165
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发表时间：
2012-05-01
影响因子：
11.5
通讯作者：
Eskens, Ferry A. L. M.
中科院分区：
文献类型：
--
作者：
Banerji, Udai;van Doorn, Leni;Eskens, Ferry A. L. M.
目的：本临床试验研究的安全性，耐受性，药代动力学（PK），和药效学（PD）的个人资料，选择性I类组蛋白去乙酰化酶inhibitors.Patients和方法：口服给药，每天一次的ESTA-3996。该I期试验采用3+3剂量递增设计。通过液相色谱-串联质谱法分析PK特征，并使用ELISA研究外周血单核细胞中的组蛋白H3乙酰化进行PD研究。39例患者接受5 mg（n = 3）、10 mg（n = 4）、20 mg（n = 3）、40 mg（n = 10）、80 mg（n = 10）、120 mg（n = 4）、和160 mg（n = 5）每日一次口服给药。观察到的剂量限制性毒性为血小板减少症（160 mg）、疲乏（80和120 mg）、血浆肌酐升高（80和120 mg）和房颤（40 mg）。曲线下面积与给药剂量成比例，40 mg剂量下的最大血浆浓度259 ng/mL超过了临床前模型中抗肿瘤疗效所需的浓度。通过组蛋白乙酰化定量测定的靶向抑制在10 mg/d剂量下显示，在40 mg剂量下最大。部分反应被认为是在一个病人与转移性胰腺腺泡carcinoma.Conclusions：考虑到毒性和PK/PD曲线，推荐的II期剂量（RP 2D）是40 mg/d。在该剂量下，CYP-3996具有良好的毒理学、PK和PD特征。目前已显示出初步的临床活性，应在进一步的临床试验中进行评估。临床癌症研究; 18（9）; 2687-94。（C）2012年AACR。
Purpose: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.Patients and Methods: CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells.Results: Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The doselimiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma.Conclusions: Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials. Clin Cancer Res; 18(9); 2687-94. (C)2012 AACR.