Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies
Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies
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DOI：
10.1200/jco.2005.14.415
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发表时间：
2005-08-10
影响因子：
45.3
通讯作者：
Meyer, MB
中科院分区：
文献类型：
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作者：
LoRusso, PM;Adjei, AA;Meyer, MB
目的本研究旨在确定CI-1040的毒性、药代动力学、药效学、最大耐受剂量（MTD）和临床活性（丝裂原活化蛋白激酶激酶）-1和MEK 2，在晚期恶性肿瘤患者中。1040以每日多次给药频率进行测试，每28天重复给药21天，最终导致连续给药，并测试食物对吸收的影响。单剂量和稳态药代动力学进行了评估，在第1周期和磷酸化细胞外受体激酶（PERK）水平进行了评估，白细胞和肿瘤组织从选定的patientsResultsSeventy-seven患者接受CI-1040的剂量水平范围从100 mg QD至800 mg tid。在试验的最高剂量水平（800 mg tid，随餐给药）下，3级虚弱具有剂量限制性。98%的药物相关不良事件的严重程度为1级或2级;最常见的毒性包括腹泻、虚弱、皮疹、恶心和呕吐。CI-1040及其活性代谢产物PD 0184264的血浆浓度在100至800 mg OD范围内以低于剂量比例的方式增加。与高脂肪餐一起给药导致药物暴露增加。MTD和推荐的II期剂量为800 mg BID，与食物同服。66例患者可评估缓解。1例胰腺癌患者实现了部分缓解，19例患者（28%）实现了疾病稳定，中位持续时间为5.5个月（范围：4至17个月）。抑制肿瘤PERK（中位数，73%;范围，46%至100%）被证明在10 patients.ConclusionCI-1040耐受性良好，在800毫克BID与食物。在该I期研究中证明了靶向抑制和抗肿瘤活性。
PurposeThis phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2, in patients with advanced malignancy.Patients and MethodsCI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (PERK) levels were assessed in WBCs and also in tumor tissue from selected patientsResultsSeventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg OD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor PERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients.ConclusionCI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.