Vogelbaum Michael A, Brewer Cathy, Barnett Gene H, Mohammadi Alireza M, Peereboom David M, Ahluwalia Manmeet S, Gao Shenqiang
1Brain Tumor and Neuro-Oncology Center and.
Departments of2Neurosurgery and.
J Neurosurg. 2018 Apr 13;130(2):476-485. doi: 10.3171/2017.10.JNS171845. Print 2019 Feb 1.
Progress in management of high-grade gliomas (HGGs) has been hampered by poor access of potential therapeutics to the CNS. The Cleveland Multiport Catheter (CMC), which deploys 4 independent delivery microcatheters, was developed to be a reliable, high-volume delivery device for delivery of therapeutic agents to the brain and other solid organs. The authors undertook this first-in-human clinical trial effort to evaluate the delivery characteristics of the CMC in patients with HGGs.
A series of pilot studies were launched after approval of a sponsor-investigator IND (investigational new drug) application to evaluate the delivery of topotecan and gadolinium-DTPA (Gd-DTPA) via the CMC in patients with recurrent HGG. The first pilot trial evaluated delivery into enhancing tumor and nonenhancing, tumor-infiltrated brain. Two catheters were placed with the use of a conventional frameless stereotactic technique following a biopsy to confirm tumor recurrence, and drug infusion was performed both intraoperatively and postoperatively for a total of 96 hours with the same rate for all microcatheters. Delivery was assessed by intermittent MRI.
Three patients were enrolled in the first pilot study. MRI demonstrated delivery from all 6 catheters (24 microcatheters). The volume of distribution (Vd) of Gd-DTPA was heavily dependent upon CMC location (enhancing vs nonenhancing) with an approximately 10-fold difference in Vd observed (p = 0.005). There were no hemorrhages related to catheter placement or removal, and all 3 patients completed the protocol-defined treatment.
The CMC is capable of providing backflow-resistant drug delivery to the brain and brain tumors. The volume of distribution is heavily dependent upon the integrity of the blood-brain barrier. Assessment of delivery is essential for development of loco-regionally applied therapeutics in the CNS.Clinical trial registration no.: NCT02278510 (clinicaltrials.gov).
潜在治疗药物难以进入中枢神经系统阻碍了高级别胶质瘤（HGG）治疗的进展。克利夫兰多端口导管（CMC）可部署4根独立的输送微导管，被开发为一种可靠的、大容量的输送装置，用于向大脑和其他实体器官输送治疗药物。作者开展了这项首次人体临床试验，以评估CMC在HGG患者中的输送特性。
在申办者-研究者的研究性新药（IND）申请获批后，开展了一系列初步研究，以评估拓扑替康和钆喷酸葡胺（Gd-DTPA）经CMC在复发性HGG患者中的输送情况。首个初步试验评估了向强化肿瘤和非强化、肿瘤浸润脑内的输送。活检确认肿瘤复发后，采用传统的无框架立体定向技术放置两根导管，并在术中和术后进行药物输注，共96小时，所有微导管的输注速率相同。通过间歇性磁共振成像（MRI）评估输送情况。
3名患者入组首个初步研究。MRI显示所有6根导管（24根微导管）均有药物输送。Gd-DTPA的分布容积（Vd）很大程度上取决于CMC的位置（强化与非强化），观察到Vd有大约10倍的差异（p = 0.005）。没有与导管放置或拔除相关的出血，所有3名患者均完成了方案规定的治疗。
CMC能够向大脑和脑肿瘤提供抗逆流药物输送。分布容积很大程度上取决于血脑屏障的完整性。评估输送情况对于中枢神经系统局部应用治疗药物的开发至关重要。临床试验注册号：NCT02278510（clinicaltrials.gov）。
