Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis
Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis
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DOI：
10.1016/j.ejca.2018.02.032
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发表时间：
2018-05-01
影响因子：
8.4
通讯作者：
Gutierrez, Maya
中科院分区：
文献类型：
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作者：
Bonneau, Claire;Paintaud, Gilles;Gutierrez, Maya
目的：轻脑膜癌（MC）通常与her2阳性乳腺癌（HER2-BC）相关，预后差，无标准化治疗。我们对HER2-BC MC患者进行了一项鞘内（IT）给药曲妥珠单抗的I期剂量递增研究，以确定最大耐受剂量（MTD），这是基于曲妥珠单抗脑脊液浓度接近常规治疗血浆浓度（30mg /L）和/或剂量限制性毒性（DLT）的实现。方法：方案计划曲妥珠单抗（30mg, 60mg， 100mg或150mg剂量水平）每周1次，疗程至少4周。16例HER2-BC MC患者接受了IT曲妥珠单抗治疗。每次注射前取脑脊液样品进行药代动力学分析。结果：我们未观察到IT曲妥珠单抗的DLT。11例患者没有因IT曲妥珠单抗引起的毒性。对于60mg或更高剂量水平，由IT曲妥珠单抗引起的轻微毒性包括头痛（2例）、恶心（2例）、呕吐（1例）、颈椎疼痛（1例）和周围神经病变（1例）。两名患者出现立即中毒，包括头痛或呕吐。在150mg剂量水平下，曲妥珠单抗的平均残余脑脊液浓度为27.9 mg/L。3例获得临床缓解，7例病情稳定，4例病情进展。结论：对于HER2-BC和MC患者，IT曲妥珠单抗的MTD和推荐的II期周剂量为150mg。使用该剂量方案治疗HER2-BC型MC的II期试验正在进行中。注册标识：临床试验。gov标识符：NCT01373710 （https://clinicaltrials. gov）。gov / ct2 /显示/ NCT01373710吗?termZtrastuzumabthornintrathecal&rank = 1)。(C) 2018 Elsevier Ltd.版权所有。
Purpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT).Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics.Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease.Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing.Registration identification: ClinicalTrials. gov Identifier: NCT01373710 (https://clinicaltrials. gov/ct2/show/NCT01373710? termZtrastuzumabthornintrathecal&rank=1). (C) 2018 Elsevier Ltd. All rights reserved.