Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies
Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies
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DOI：
10.1200/jco.2002.01.133
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发表时间：
2002-11-15
影响因子：
45.3
通讯作者：
Soignet, SL
中科院分区：
文献类型：
--
作者：
Orlowski, RZ;Stinchcombe, TE;Soignet, SL
目的：确定蛋白酶体抑制剂硼替佐米的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药效学（PD）（以前称为PS-341）治疗难治性恶性血液病患者的疗效。患者接受PS-341，每周两次，剂量为0.40、1.04、1.20或1.38 mg/m2，持续4周，随后休息2周。PS-341的PD通过测量全血20 S蛋白酶体activity.Results：27例患者接受了293次PS-341，包括24个完整周期。剂量高于1.04 mg/m2 MTD时，归因于PS-341的DLT包括血小板减少症、低钠血症、低钾血症、疲乏和不适。在接受额外治疗的10例患者中，有3例在第2周期出现严重可逆不良事件，包括1例体位性低血压发作，1例全身性超敏反应，1例丙型肝炎患者发生4级转氨酶升高，大量摄入对乙酰氨基酚。PD研究显示PS-341以时间依赖性方式诱导205蛋白酶体抑制，并且该抑制还与PS-341的剂量（mg/m2）和绝对剂量相关。在9例完成一个治疗周期的重度浆细胞恶液质患者中，有1例完全缓解，另外8例副蛋白水平和/或骨髓浆细胞增多症降低。结论：PS-341在1.04 mg/m2剂量下耐受性良好，但需要监测患者的电解质异常和晚期毒性。需要进行其他研究，以确定剂量/体表面积的结合是否产生优于未归一化给药的上级PD模型。在这项研究中，PS-341显示出对难治性多发性骨髓瘤和可能的非霍奇金淋巴瘤的活性，值得在这些人群中进一步研究。(C)2002年，美国临床肿瘤学会。
Purpose : To determine the maximum-tolerated dose (MTD),dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.Patients and Methods: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.Results: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokolemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 205 proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.Conclusion: PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations. (C) 2002 by American Society of Clinical Oncology.