Proteasome inhibition with bortezomib (PS-341): A phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
Proteasome inhibition with bortezomib (PS-341): A phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle
复制标题
DOI：
10.1200/jco.2005.01.136
复制
发表时间：
2005-09-01
影响因子：
45.3
通讯作者：
Muggia, FM
中科院分区：
文献类型：
--
作者：
Hamilton, AL;Eder, JP;Muggia, FM
目的 我们进行了每两周一次每天 (D) 1 和 D4 硼替佐米给药的 I 期研究，以确定推荐的 II 期剂量和毒性特征，以及获得的 20S 蛋白酶体抑制程度。 患者和方法 实体瘤或淋巴瘤患者在 D1 和 D4 接受 0.25 至 1.9 mg/m(2) 的硼替佐米治疗，每 2 周一次。在第 1 周期的基线以及给药后 1、4 和 24 小时测定血液中的 20S 蛋白酶体水平。结果 在每两周一次的 D1 和 D4 计划中，剂量限制性毒性 (DLT) 在 1.75 和 1.9 mg/m(2) 剂量水平下很明显，最常见于接受个体总剂量 >= 3.0 mg 的患者。主要的 DLT 是在较高剂量下和先前接触过神经毒剂的患者中明显的周围神经病变。其他 DLT 包括腹泻和疲劳；还注意到 3 级血小板减少症。 20S 蛋白酶体活性的可逆抑制是剂量依赖性的，最适合每个分数的总剂量 (mg)，而不是 mg/m(2)；每隔一周在 D1 和 D4 给予 3.0 至 3.5 mg 的剂量，可抑制 70% 的基线活动。在黑色素瘤、非小细胞肺癌和肾细胞癌患者中观察到未证实部分缓解的抗肿瘤作用。结论硼替佐米 (PS-341) 是一种新型抗肿瘤药物，在剂量不超过 3.0 mg（相当于 1.75 mg/m(2)）时耐受性良好，每隔一周在 D1 和 D4 重复一次。该剂量与 20S 蛋白酶体活性 70% 的抑制相关。 DLT 包括神经病、疲劳和腹泻。
Purpose We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained.Patients and Methods Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m(2) on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1.Results On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m(2) dose levels, most commonly in patients receiving individual total doses >= 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m(2); 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma.Conclusion Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m(2)), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.