A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer
A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer
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DOI：
10.1007/s10549-013-2510-5
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发表时间：
2013-05-01
影响因子：
3.8
通讯作者：
Baselga, Jose
中科院分区：
文献类型：
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作者：
Modi, Shanu;Saura, Cristina;Baselga, Jose
热休克蛋白90 （Hsp90）促进HER2的成熟和稳定。Hsp90抑制剂联合曲妥珠单抗在HER2+乳腺癌患者中显示出抗肿瘤作用。患有可测量的局部晚期或转移性HER2+乳腺癌且既往接受过曲妥珠单抗治疗的成年人参加了一项2期试验，每周使用300 mg/m(2)利阿霉素HCl（一种有效的Hsp90抑制剂），每3周使用6 mg/kg曲妥珠单抗。Simon的两阶段设计通过剂量限制毒性（DLT）和反应率来确定试验扩展。评估药代动力学和心电图。26例患者入组，中位年龄52.5岁（范围33-72），既往化疗方案中位数为6种（范围2-20）。在研究中，患者接受了中位数为3个治疗周期（范围1-12）。未观察到dlt。大多数不良事件（ae）为1级或2级；常见的治疗相关不良反应包括疲劳（46%）、恶心（31%）和腹泻（23%）。1例患者出现与治疗相关的严重不良反应，包括1级腹泻和3级低钾血症。3级转氨酶升高发生在1例（4%）同时患有转移性肝病的患者。16例患者（62%）病情稳定，中位研究持续时间为2.4个月（范围1.1-8.2）。未观察到确诊的反应。每周300 mg/mA(2)的盐酸雷塔霉素联合曲妥珠单抗耐受性良好，无明显毒性。观察到适度的临床活动，但不符合试验扩展的标准。研究中患者的安全性表明盐酸再阿斯霉素剂量不足可能会限制疗效。使用更高剂量的研究正在进行中。
Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m(2) retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon's two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33-72) enrolled with a median of six prior chemotherapeutic regimens (range 2-20). On study, patients received a median of three treatment cycles (range 1-12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1-8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/mA(2) weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing.