Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: A phase I AIDS malignancy consortium study
Matrix metalloproteinase inhibitor COL-3 in the treatment of AIDS-related Kaposi's sarcoma: A phase I AIDS malignancy consortium study
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DOI：
10.1200/jco.20.1.153
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发表时间：
2002-01-01
影响因子：
45.3
通讯作者：
Dezube, BJ
中科院分区：
文献类型：
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作者：
Cianfrocca, M;Cooley, TP;Dezube, BJ
目的：基质金属蛋白酶（MMPs）在卡波西肉瘤（KS）细胞中过度表达，参与肿瘤的侵袭和转移。主要目的是确定MMP抑制剂COL-3在艾滋病相关KS患者中的安全性和毒性。次要目的是评估肿瘤反应、药代动力学以及血液中MMP-2、MMP-9、血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）水平的变化。患者和方法：COL-3每天口服一次，并在3至6名受试者的队列中逐步增加剂量。排除有症状性内脏KS或严重肿瘤相关水肿的患者。抗逆转录病毒治疗是允许的，但不是必需的。研究终点为3级或4级毒性或进展性KS。连续采集血液标本检测药代动力学和MMP-2、MMP-9、VEGF和bFGF水平。结果：18例患者接受COL-3治疗，剂量组分别为25、50和70 mg/m(2)/d。既往有17例患者（94%）接受过KS治疗。6例患者报告了col3相关的3级或4级不良事件，包括光敏、皮疹和头痛。有1例完全缓解和7例部分缓解，总缓解率为44%，中位缓解持续时间为25周以上。COL-3的中位半衰期为39.3小时（范围4.1至251.1小时）。有反应者和无反应者在治疗时血清MMP-2水平从基线到最低值的变化方面存在显著差异（P = 0.037）。结论：每日1次口服COL-3治疗艾滋病相关KS患者耐受性良好。最常见的不良事件是剂量相关的光敏性。注意到抗肿瘤活性。进一步评估COL-3治疗KS是有必要的。(C) 2001年美国临床肿瘤学会。
Purpose: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and are over-expressed in Kaposi's sarcoma (KS) cells. The primary aim was to define the safety and toxicity of the MMP inhibitor COL-3 in patients with AIDS-related KS. Secondary aims were to evaluate tumor response, pharmacokinetics, and changes in blood levels of MMP-2, MMP-9, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF).Patients and Methods: COL-3 was administered orally once daily, and doses were escalated in cohorts of three to six subjects. Patients with symptomatic visceral KS or severe tumor-associated edema were excluded. Antiretroviral therapy was permitted but not required. Study end points were grade 3 or 4 toxicity or progressive KS. Serial blood specimens were obtained for pharmacokinetics and levels of MMP-2, MMP-9, VEGF, and bFGF.Results: Eighteen patients received COL-3 in dosing cohorts of 25, 50, and 70 mg/m(2)/d. Prior KS therapy was reported by 17 patients (94%). COL-3-related grade 3 or 4 adverse events were reported by six patients and included photosensitivity, rash, and headache. There was one complete response and seven partial responses, for an overall response rate of 44%, with a median response duration of 25+ weeks. The median COL-3 half-life was 39.3 hours (range, 4.1 to 251.1 hours). There was a significant difference between responders and nonresponders with respect to the change in MMP-2 serum levels from baseline to minimum value on treatment (P = .037).Conclusion: COL-3 administered orally once daily to patients with AIDS-related KS is reasonably well tolerated. The most common adverse event was dose-related photosensitivity. Antitumor activity was noted. Further evaluation of COL-3 for the treatment of KS is warranted. (C) 2001 by American Society of Clinical Oncology.