Levitt N C, Eskens F A, O'Byrne K J, Propper D J, Denis L J, Owen S J, Choi L, Foekens J A, Wilner S, Wood J M, Nakajima M, Talbot D C, Steward W P, Harris A L, Verweij J
Imperial Cancer Research Fund Unit, Churchill Hospital, Oxford OX3 FLJ, United Kingdom.
Clin Cancer Res. 2001 Jul;7(7):1912-22.
This Phase I study of MMI270, an p.o. administered matrix metalloproteinase inhibitor, assessed toxicity, pharmacokinetics, and tumor response data and investigated markers of biological activity to recommend a dose for Phase II studies. MMI270 was administered continuously at seven dose levels (50 mg once daily to 600 mg three times/day). Patients were evaluated for toxicity and tumor response, and blood and urine samples were taken for pharmacokinetics, bone resorption markers, direct targets of the inhibitor [matrix metalloproteinase-2 (MMP-2), MMP-8, and MMP-9], indirect targets [tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, basic fibroblast growth factor, vascular endothelial growth factor, vascular cell adhesion molecule-1, soluble urokinase plasminogen activator receptor, and cathepsins B and H] and for a tumor necrosis factor-alpha cytokine release assay. Ninety-two patients were entered. There was no myelotoxicity. Eighteen patients developed a widespread maculopapular rash, which increased in frequency and severity at doses > or = 300 mg bid. Thirty nine patients developed musculoskeletal side effects, which were related to duration of treatment, not to dose level. Pharmacokinetics were linear, and MMI270 was rapidly absorbed and eliminated with minimal accumulation on chronic dosing. Sustained plasma concentrations in excess of 4 x mean IC(50) for the target enzymes were observed at dose levels > or = 150 mg bid. There were no tumor regressions; however, 19 patients had stable disease for > or = 90 days. There was a dose-response increase of MMP-2 and TIMP-1 with MMI270. Transient effects on the bone resorption markers were detected. MMI270 was generally well tolerated, with adequate plasma levels for target enzyme inhibition. The two main toxicities were rash, resulting in a maximum tolerated dose of 300 mg bid and musculoskeletal side effects. Biological marker data indicate drug effects. The rise in TIMP-1 suggests that a reflex rise in inhibitors could modify the effects of MMI270. The recommended Phase II dose is 300 mg bid.
本I期研究针对口服给药的基质金属蛋白酶抑制剂MMI270，评估了其毒性、药代动力学和肿瘤反应数据，并研究了生物活性标志物，以推荐II期研究的剂量。MMI270以七个剂量水平连续给药（每日一次50毫克至每日三次600毫克）。对患者进行毒性和肿瘤反应评估，并采集血液和尿液样本用于药代动力学、骨吸收标志物、抑制剂的直接靶点[基质金属蛋白酶-2（MMP-2）、MMP-8和MMP-9]、间接靶点[金属蛋白酶组织抑制剂-1（TIMP-1）、TIMP-2、碱性成纤维细胞生长因子、血管内皮生长因子、血管细胞粘附分子-1、可溶性尿激酶型纤溶酶原激活剂受体以及组织蛋白酶B和H]检测，以及进行肿瘤坏死因子-α细胞因子释放试验。共纳入92例患者。未观察到骨髓毒性。18例患者出现广泛的斑丘疹，在剂量≥300毫克每日两次时，皮疹的频率和严重程度增加。39例患者出现肌肉骨骼副作用，这与治疗持续时间有关，而非剂量水平。药代动力学呈线性，MMI270吸收迅速，消除快，长期给药时蓄积极少。在剂量≥150毫克每日两次时，观察到血浆浓度持续超过目标酶平均IC50的4倍。未观察到肿瘤消退；然而，19例患者疾病稳定≥90天。MMI270使MMP-2和TIMP-1呈剂量反应性增加。检测到对骨吸收标志物的短暂影响。MMI270总体耐受性良好，血浆水平足以抑制目标酶。两种主要毒性为皮疹，导致最大耐受剂量为300毫克每日两次，以及肌肉骨骼副作用。生物标志物数据表明药物有作用。TIMP-1升高表明抑制剂的反射性升高可能改变MMI270的作用。推荐的II期剂量为300毫克每日两次。
