Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study
Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study
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DOI：
10.1111/j.1365-2141.2011.08664.x
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发表时间：
2011-06-01
影响因子：
6.5
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Richardson, Paul G.;Chanan-Khan, Asher A.;Anderson, Kenneth C.
这项开放标签、剂量递增、多中心1/2期试验旨在确定热休克蛋白90（HSP 90）抑制剂tanespimycin（100-340 mg/m2）+硼替佐米（0中心点7-1中心点3 mg/m2）在每个21天周期的第1、4、8和11天给药的安全性和耐受性。在最高测试剂量的坦司匹霉素340 mg/m2和硼替佐米1个中心点3 mg/m2下发生2期扩增。入组了72例复发性或复发性和难治性多发性骨髓瘤（MM）患者（中位年龄60岁）; 63例患者（89%）完成了研究。坦司匹霉素联合硼替佐米耐受性良好;少数患者发生显著的中性粒细胞减少、便秘和厌食（< 10%），无患者发生严重的周围神经病变。在67例疗效可评价的患者中，有2例（3%）完全缓解和8例（12%）部分缓解，客观缓解率（ORR）为27%，包括8例（12%）轻微缓解。硼替佐米初治患者的缓解率最高，并且在所有患者亚组（包括硼替佐米难治性疾病患者）中证明是持久的。药效学分析表明，坦螺旋霉素加硼替佐米有效地抑制蛋白酶体，如20 S蛋白酶体活性降低所证明，并抑制HSP 90，如HSP 70表达增加所反映。本研究的结果支持在MM中进行这种联合方法的额外研究。
P>This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m2) + bortezomib (0 center dot 7-1 center dot 3 mg/m2) given on days 1, 4, 8 and 11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m2 and bortezomib at 1 center dot 3 mg/m2. Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients experienced significant neutropenia, constipation and anorexia (< 10%), and no patients developed severe peripheral neuropathy. Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support additional studies of this combination approach in MM.