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

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OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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)

ABBREVIATIONS AE = adverse event; BBB = blood-brain barrier; CED = convection-enhanced delivery; CMC = Cleveland Multiport Catheter; GBM = glioblastoma; HGG = high-grade glioma; IND = investigational new drug; IRB = institutional review board; IV = intravenous; KPS = Karnofsky Performance Status; NSDU = neurological step-down unit; OR = operating room; PTFE = polytetrafluoroethylene; TMZ = temozolomide; Vd = volume of distribution.

Article Information

Correspondence Michael A. Vogelbaum: Cleveland Clinic, Cleveland, OH. vogelbm@ccf.org.

INCLUDE WHEN CITING Published online April 13, 2018; DOI: 10.3171/2017.10.JNS171845.

Disclosures Funding for investigational aspects of treatment was provided by Infuseon Therapeutics, Inc. The investigators did not receive any salary support or other direct financial support.

Dr. Vogelbaum (M.A.V.) is an inventor of the Cleveland Multiport Catheter (CMC) and has license and royalty interests in it. He is co-founder and chief medical officer of Infuseon Therapeutics, Inc., sponsor of the study, and has indirect equity and royalty interests in Infuseon. The Sponsor-Investigator IND for this study was held by M.A.V. The Cleveland Clinic Innovation Management and Conflict of Interest Committee found compelling circumstances for M.A.V.’s participation in the research related to Infuseon, a Cleveland Clinic spin-off company formed around the CMC, which he invented. His participation in the research related to the company is subject to a conflict management plan reviewed and approved by the Innovation Management and Conflict of Interest Committee. The plan requires broad disclosure of the institutional and individual financial interests, that informed consent is conducted by a non-conflicted research nurse in addition to M.A.V., that review of subject eligibility is done by a non-conflicted clinician, that M.A.V. will not have direct access to the research data, that image analysis is conducted by a non-conflicted physician, and review and monitoring of compliance by the Innovation Management and Conflict of Interest Committee. None of the other authors have a financial interest in the CMC or in Infuseon.

Dr. Ahluwalia reports consultant relationships with Monteris Medical, Abbvie, Astrazeneca, and CBT Pharmaceuticals.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Illustration of the Cleveland Multiport Catheter in the (upper) undeployed state, and (lower) with its microcatheters deployed. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2013–2017. All rights reserved.

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    Upper: Photograph of the “ramp” accessory used to secure the CMC in place. Lower: Photograph of the CMC within the “ramp” accessory.

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    Axial MPRAGE MR images showing the progress of the intraoperative CED infusions. Gd-DTPA was co-administered with topotecan by CED. No IV contrast agent was administered. ET = enhancing tumor; NET = nonenhancing tumor.

  • View in gallery

    Axial MPRAGE MR images showing the peak Vd for each patient. Images are centered on the catheters placed in enhancing tumor (ET) or nonenhancing tumor (NET). For patient 1, the Vds for the 2 CMCs overlapped and so only 1 image is shown.

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    Graphs showing the change in Vd over the course of the 4-day infusions. Upper: CMC placed in nonenhancing tumor. Lower: CMC placed in enhancing tumor.

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