Convection-enhanced delivery of topotecan into high grade glioma

Topotecan, is an ideal drug for convection-enhanced delivery (CED) of gliomas because (1) it is cytotoxic to glioma cells and nontoxic to normal brain; (2) topoisomerase I levels are higher in glioma cells and tumor tissue than in normal brain; and (3) it is a natural-product drug with high molecular weight and thus should minimally traverse the BBB from the brain to the systemic circulation ¹⁾ ²⁾ ³⁾ ⁴⁾

Malignant gliomas are locally invasive but rarely metastatic, as evidenced by predominately local recurrences, making them vulnerable to local regional delivery approaches such as convection-enhanced delivery (CED) ⁵⁾.

Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials ⁶⁾.

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.METHODSA 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.RESULTSThree 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.CONCLUSIONSThe 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) ⁷⁾.

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Bruce JN, Falavigna A, Johnson JP, et al. Intracerebral clysis in a rat glioma model. Neurosurgery. 2000;46(3):683–691.

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Matsumoto Y, Fujiwara T, Honjo Y, Sasaoka N, Tsuchida T, Nagao S. Quantitative analysis of DNA topoisomerase I activity in human and rat glioma: characterization and mechanism of resistance to antitopoisomerase chemical, camptothecin-11. J Surg Oncol. 1993;53(2):97–103.

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Bruce JN, Fine RL, Canoll P, Yun J, Kennedy BC, Rosenfeld SS, Sands SA, Surapaneni K, Lai R, Yanes CL, Bagiella E, DeLaPaz RL. Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan. Neurosurgery. 2011 Dec;69(6):1272-9; discussion 1279-80. doi: 10.1227/NEU.0b013e3182233e24. PubMed PMID: 21562434; PubMed Central PMCID: PMC4940854.

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Vogelbaum MA, Brewer C, Barnett GH, Mohammadi AM, Peereboom DM, Ahluwalia MS, Gao S. First-in-human evaluation of the Cleveland Multiport Catheter for convection-enhanced delivery of topotecan in recurrent high-grade glioma: results of pilot trial 1. J Neurosurg. 2018 Apr 1:1-10. doi: 10.3171/2017.10.JNS171845. [Epub ahead of print] PubMed PMID: 29652233.