亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Repeated blood–brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial

医学 紫杉醇 微气泡 卡铂 药代动力学 白蛋白 胶质瘤 临床终点 人口 泌尿科 血脑屏障 超声波 外科 内科学 临床试验 化疗 放射科 癌症研究 顺铂 中枢神经系统 环境卫生
作者
Adam M. Sonabend,Andrew Gould,Christina Amidei,Rachel Ward,Karyn A Schmidt,Daniel Y. Zhang,Cristal Gomez,John F. Bebawy,Benjamin P. Liu,Guillaume Bouchoux,Carole Desseaux,Irene Helenowski,Rimas V. Lukas,Karan Dixit,Priya Kumthekar,Víctor A. Arrieta,Maciej S. Lesniak,Alexandre Carpentier,Hui Zhang,Miguel Muzzio
出处
期刊:Lancet Oncology [Elsevier BV]
卷期号:24 (5): 509-522 被引量:130
标识
DOI:10.1016/s1470-2045(23)00112-2
摘要

Summary

Background

Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood–brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.

Methods

We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood–brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual.

Findings

17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12–12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40–215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood–brain barrier opening were done (median 3 cycles per patient [range 2–6]). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood–brain barrier opening was most commonly associated with immediate yet transient grade 1–2 headache (12 [71%] of 17 patients). The most common grade 3–4 treatment-emergent adverse events were neutropenia (eight [47%]), leukopenia (five [29%]), and hypertension (five [29%]). No treatment-related deaths occurred during the study. Imaging analysis showed blood–brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 μM [95% CI 0·022–0·063] in non-sonicated brain to 0·139 μM [0·083–0·232] in sonicated brain [3·7-times increase], p<0·0001) and carboplatin (from 0·991 μM [0·562–1·747] in non-sonicated brain to 5·878 μM [3·462–9·980] μM in sonicated brain [5·9-times increase], p=0·0001).

Interpretation

LIPU-MB using a skull-implantable ultrasound device transiently opens the blood–brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing.

Funding

National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.

Video Abstract

Repeated blood–brain barrier opening with an implantable ultrasound device
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
传奇3应助科研通管家采纳,获得10
4秒前
英俊的铭应助科研通管家采纳,获得10
4秒前
17秒前
科研通AI5应助Betty采纳,获得10
17秒前
MchemG应助彩色的谷云采纳,获得10
25秒前
吴彦祖完成签到,获得积分10
48秒前
xixilulixiu完成签到 ,获得积分10
50秒前
52秒前
1分钟前
tree发布了新的文献求助10
1分钟前
大模型应助tree采纳,获得10
1分钟前
Lucas应助科研通管家采纳,获得10
2分钟前
科研通AI2S应助科研通管家采纳,获得10
2分钟前
tree完成签到,获得积分20
2分钟前
辉辉完成签到,获得积分10
2分钟前
wodetaiyangLLL完成签到 ,获得积分10
3分钟前
黑白完成签到 ,获得积分10
5分钟前
5分钟前
Qian完成签到 ,获得积分10
5分钟前
情怀应助Ying采纳,获得20
6分钟前
6分钟前
6分钟前
科研通AI5应助忧虑的安青采纳,获得10
6分钟前
juejue333完成签到,获得积分10
6分钟前
6分钟前
6分钟前
Ying发布了新的文献求助20
7分钟前
7分钟前
Betty发布了新的文献求助10
7分钟前
Betty完成签到,获得积分10
7分钟前
科目三应助科研通管家采纳,获得10
8分钟前
科研通AI2S应助科研通管家采纳,获得10
8分钟前
SciGPT应助科研通管家采纳,获得10
8分钟前
笨笨完成签到,获得积分10
8分钟前
8分钟前
8分钟前
思源应助嘿嘿嘿侦探社采纳,获得10
8分钟前
8分钟前
8分钟前
9分钟前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Cognitive Neuroscience: The Biology of the Mind 1000
Technical Brochure TB 814: LPIT applications in HV gas insulated switchgear 1000
Immigrant Incorporation in East Asian Democracies 600
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
A Preliminary Study on Correlation Between Independent Components of Facial Thermal Images and Subjective Assessment of Chronic Stress 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3968504
求助须知:如何正确求助?哪些是违规求助? 3513278
关于积分的说明 11167234
捐赠科研通 3248660
什么是DOI,文献DOI怎么找? 1794386
邀请新用户注册赠送积分活动 875030
科研通“疑难数据库(出版商)”最低求助积分说明 804638