Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial

医学 拓扑替康 外科 胶质瘤 不利影响 临床试验 化疗 养生 临床研究阶段 临床终点 肿瘤科 内科学 癌症研究
作者
Eleonora F. Spinazzi,Michael Argenziano,Pavan S. Upadhyayula,Matei A. Banu,Justin A. Neira,Dominique Higgins,Peter Wu,Brianna Pereira,Aayushi Mahajan,Nelson Humala,Osama Al‐Dalahmah,Wenting Zhao,Akshay Save,Brian J.A. Gill,Deborah Boyett,Tamara Marie,Julia Furnari,Tejaswi Sudhakar,Sylwia A. Stopka,Michael S. Regan,Vanessa V. Catania,Laura Good,Stergios Zacharoulis,Meenu Behl,Petros Petridis,Sachin Jambawalikar,Akiva Mintz,Angela Lignelli,Nathalie Y.R. Agar,Peter A. Sims,Mary Welch,Andrew B. Lassman,Fábio M. Iwamoto,Randy S. D’Amico,Jack Grinband,Peter Canoll,Jeffrey N. Bruce
出处
期刊:Lancet Oncology [Elsevier BV]
卷期号:23 (11): 1409-1418 被引量:43
标识
DOI:10.1016/s1470-2045(22)00599-x
摘要

Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.
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
刚刚
安静发布了新的文献求助10
1秒前
上官若男应助PANYIAO采纳,获得10
2秒前
5秒前
tingting9发布了新的文献求助10
5秒前
5秒前
6秒前
6秒前
Akim应助高手采纳,获得10
6秒前
6秒前
李健的小迷弟应助ZZZ采纳,获得10
6秒前
你好呀嘻嘻完成签到 ,获得积分10
6秒前
zwxzghgz完成签到,获得积分10
7秒前
hello发布了新的文献求助10
11秒前
11秒前
11秒前
11秒前
crazy完成签到,获得积分10
12秒前
咩咩羊发布了新的文献求助10
13秒前
易儿发布了新的文献求助10
13秒前
PANYIAO发布了新的文献求助10
14秒前
李彪完成签到,获得积分20
14秒前
小柒完成签到,获得积分10
15秒前
Lucas应助13223456采纳,获得10
16秒前
18秒前
chris发布了新的文献求助50
18秒前
简单面包完成签到,获得积分10
21秒前
踏实的老四完成签到,获得积分20
21秒前
23秒前
洪汉发布了新的文献求助50
25秒前
26秒前
27秒前
hahahah发布了新的文献求助20
28秒前
Hello应助猪猪hero采纳,获得10
29秒前
飞快的夜天完成签到 ,获得积分10
29秒前
29秒前
Quinna发布了新的文献求助10
32秒前
33秒前
34秒前
ZZICU完成签到,获得积分10
35秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
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 3989242
求助须知:如何正确求助?哪些是违规求助? 3531393
关于积分的说明 11253753
捐赠科研通 3270010
什么是DOI,文献DOI怎么找? 1804868
邀请新用户注册赠送积分活动 882084
科研通“疑难数据库(出版商)”最低求助积分说明 809136