Results of a Pilot Trial of Infusion Rate Escalation During Convection Enhanced Delivery of Topotecan with a Multiport Catheter

Results of a Pilot Trial of Infusion Rate Escalation During Convection Enhanced Delivery of Topotecan with a Multiport Catheter | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Results of a Pilot Trial of Infusion Rate Escalation During Convection Enhanced Delivery of Topotecan with a Multiport Catheter James K. C. Liu, Nam Tran, Cecily Piteo, Alisa Peinhardt, Michael A. Vogelbaum This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5790058/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Volume of distribution (Vd) during convection enhanced delivery is impacted by the physical characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage. Methods: A single center, IRB-approved pilot study was conducted to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent high-grade glioma. A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed. Results: Three patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events. The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation. Conclusion: Increasing the rate of infusion can allow for larger volume of distribution into enhancing tumor tissue. Health sciences/Neurology/Neurological disorders/Cns cancer Health sciences/Oncology/Surgical oncology Glioblastoma Convection Enhanced Delivery Clinical Trial Surgical Innovation Figures Figure 1 Figure 2 INTRODUCTION Glioblastoma (GBM), the most common primary malignant brain tumor, remains incurable with median survival rates generally less than 2 years, and a 5-year survival rate of less than 5% [ 1 , 2 ]. Few therapies are approved by the FDA specifically for the treatment of newly-diagnosed GBM, and no FDA-approved treatment has shown the ability to extend survival in recurrent GBM (rGBM)[ 3 ]. There are myriad reasons for the failure of multiple approaches to improving the outcome of patients with GBM including intra-tumoral genomic heterogeneity, tumor-induced systemic and local immunosuppression, and elevated expression of drug resistance pumps/DNA repair mechanisms. While these mechanisms of resistance may be shared with other cancers, GBM has a unique form of protection from therapy via the presence of blood-brain barrier (BBB) and blood-tumor barrier (BTB)[ 4 , 5 ]. These barriers block most classes of therapeutics from accessing tumor cells at therapeutic concentrations when treatments are given by conventional routes of administration (oral or IV). Direct administration of therapeutics to the site of disease within the brain has emerged as an alternative route of therapeutic delivery[ 6 , 7 ]. One of the most widely used approaches used for direct therapeutic delivery to the brain is convection enhanced delivery (CED)[ 8 , 9 ]. The earliest clinical trials that involved the use of CED as a delivery mechanism failed to demonstrate clinical benefit; however, subsequent studies that included the use of tracers that could be imaged in real time indicated that a major source of failure related to the use of delivery catheters that did not have the proper technical design characteristics needed to ensure successful delivery via this mechanism[ 10 – 14 ]. More recent clinical trials performed with the use of CED-optimized technologies have demonstrated successful therapeutic delivery, confirmed with the use of a variety of imaging modalities[ 14 – 17 ]. One such delivery technology is the Cleveland Multiport Catheter (CMC), which has been shown to successfully delivery a combination of topotecan and gadolinium-DTPA (gd-DTPA) in patients with recurrent GBM (rGBM)[ 14 ]. In that study, there was a distinct difference in the volume of distribution (Vd) achieved with the rate and volume of infusion (Vi) specified in the protocol used in the study protocol when a CMC was placed into contrast enhancing (bulk) tumor versus non-contrast enhancing tumor infiltrated brain. This discrepancy reflected the fact that the efflux rate of enhancing tumor, where the “leaky” vascular system can rapidly carry away infusate thereby limiting its dispersion, is much higher than that of non-enhancing tumor, where the BBB remains intact thereby allowing for more uninterrupted infusate dispersion[ 14 ]. The protocol used for that study did not permit escalation of the infusion rate. To investigate whether we could safely and effectively treat enhancing tumor using higher infusion rates, we performed a rate escalation study using a single CMC. METHODS This pilot trial was performed under the US Food and Drug Administration’s Investigational New Drug (IND) process (Sponsor-Investigator IND #117,240 issued to MAV). It was a single arm, prospective, open-label therapeutic trial approved by the Moffitt Cancer Center institutional review board and carried out in accordance with the Declaration of Helsinki. All patients signed a study-specific written informed consent, which included disclosure of the Sponsor-Investigator’s financial conflict of interest (the Sponsor-Investigator had an institutionally approved conflict of interest management plan in place, which was periodically audited by institutional personnel). All study procedures were carried out by financially non-conflicted site personnel. This study was registered at ClinicalTrials.gov on 25/4/2019 (NCT03927274). The primary objective of this study was to investigate, by MRI, the spatial and temporal distribution of topotecan with Gd-DTPA in enhancing tumor administered intra-operatively by CED via a single implanted CMC, and to investigate the influence of rate on the Vd. Secondary objectives included evaluation of the extent of backflow around the implanted catheter, assessment of safety, tolerability and toxicity of topotecan administered via CED, and evaluation of the activity of topotecan administered via CED to patients with rGBM. Inclusion and Exclusion Criteria Patients had to meet all of the following inclusion criteria: 1) pathologically confirmed WHO grade III or IV (high grade) glioma (HGG) that has undergone prior surgical biopsy or resection and treated with adjuvant chemoradiotherapy; 2) Imaging-based evidence of recurrence or progression with a plan to perform stereotactic biopsy for confirmation of recurrence/progression and no requirement for surgical resection to relieve clinically-significant mass effect; 3) age > = 18 years; 4) Karnofsky Performance Status of 70–100; laboratory values that were permissible for a cranial neurosurgical procedure. Key exclusion criteria included diffuse subependymal or CSF disease; tumors involving the posterior fossa or both hemispheres; positive pregnancy test in females; radiation or chemotherapy treatment within 4 weeks of study enrollment; active infection; or inability to undergo magnetic resonance imaging. Investigational Procedures A clinically indicated stereotactic biopsy was performed under general endotracheal anesthesia (GETA) with use of a frameless image guidance surgical navigation system (Brainlab, Germany). A frozen section was evaluated by a board certified neuropathologist, and when the diagnosis of recurrent HGG was determined, one CMC catheter primed with gd-DTPA (5 mM) was stereotactically placed via the same burr hole as the biopsy and secured in place as described in a prior report (Fig. 1)[ 14 ]. While under GETA, the patients were then taken to an adjacent MRI suite. A baseline scan was obtained and then each of the 4 microcatheters of the CMC was attached, with use of sterile technique, to an infusion line pre-primed with the investigational solution (topotecan (0.05 mg/mL) mixed with gd-DTPA (5 mM)) connected to a 10 cc syringe mounted in a Medfusion 3500 syringe pump. The initial rate of infusion for the first patient was 5 microliters/minute/microcatheter and the protocol permitted rate increases as directed by the investigator team after review of the distribution of gd-DTPA visualized on intermittent non-contrast MRIs that were performed approximately every 30 minutes. A magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence was used to provide visualization of the infused contrast agent on 1mm volumetrically acquired image slices. The infusions were continued until either the bulk (enhancing) tumor was fully covered by the infusion, or 4 hours of infusion time was reached; whichever was earliest. Each subsequent patient’s infusions were started at a rate of 5 microliters/minute/microcatheter higher than the previous patient, so long as backflow had not been observed at that rate in previous patients. Evaluation of the primary endpoint (Vd of the co-infused gd-DTPA and % coverage of the enhancing tumor volume) was performed with the use of Brainlab iPlan. The Vd of gd-DTPA was used as a surrogate for topotecan distribution. Safety was evaluated with the use of CTCAE v.4.0 and causality was determined by investigators who did not have financial conflicts (JKCL, NT and CP). Original data is provided within the supplementary information files. Figure 1 Cleveland Multiport catheter following intracranial placement through a single burr hole RESULTS Three patients were treated under this pilot protocol between June, 2019 and February, 2023. The trial was closed in 2023 as the sponsor suspended operations. Demographic data for the patients is shown in Table 1 . Each of the patients had a recurrent glioblastoma that had been treated previously with surgical resection, standard dose external beam photon radiotherapy, and temozolomide chemotherapy. The target tumor volumes ranged from 1.4 to 4.65 cc, and a single CMC was placed in each case. Infusion data are shown in Table 2 . For patient 1, the initial infusion rate was 5 microliters per minute per microcatheter (m/m/m), and the maximum rate used was 15 m/m/m. The total volume of infusion (Vi) for the 4 microcatheters was 9.9 cc and the resulting volume of distribution (Vd), as measured by the volume of infused Gd-DTPA signal was 12.8 cc for a Vd/Vi ratio of 1.3. While there was coverage of both enhancing tumor and surrounding tumor infiltrated brain, the pattern of distribution was inhomogeneous and only 56% of the enhancing tumor was covered. Table 1 Patient demographics Patient 1 Patient 2 Patient 3 Gender Male Male Male Age 66 60 61 Diagnosis GBM GBM GBM MGMT methylated unmethylated Unmethylated Tumor Location Left temporal Right parietal Left temporal Table 2 Infusion data Tumor Volume Distributed Volume (Vd) Infused Volume (Vi) Vd/Vi Target Coverage Volume % Target Coverage Patient 1 1.4 12.8 9.9 1.3 0.79 56% Patient 2 3.35 12.0 9.9 1.2 2.65 79% Patient 3 4.65 8.63 12.366 0.7 2.29 49% For patient 2, the initial rate started at 10 m/m/m and the maximum rate was 20 m/m/m. The total Vi remained at 9.9 cc and the Vd was 12.0 cc for a Vd/Vi ratio of 1.2. In this case, 79% of the enhancing tumor was covered, along with surrounding non-enhancing tumor infiltrated brain. Patient 3’s infusion started at 5 m/m/m and the maximum rate was 20 m/m/m. Unfortunately, there was extensive flow into the lateral ventricle and into the subarachnoid space from 2 of the microcatheters, which reflected a less-than-ideal catheter placement. Only 49% of the target enhancing tumor was covered and the Vd/Vi ratio was 0.7. Figure 2 shows examples of the maximal coverage obtained from each of the infusions. Figure 2 Final infusion imaging. T1 weighted MRI of patient 1 (a), patient 2(b), and patient 3 (c) All of the infusions were well tolerated. There were a total of 35 adverse events (AEs) in the 3 patients, of which 19 were deemed unrelated to the drug or device by the treating physician. Of the other AEs, there were 3 grade 1 and one grade 2 AEs deemed possibly related to the study treatment, all of which recovered without intervention. There were three grade 3 AEs, two of which were in one patient. These consisted of one case of leukocystosis, deemed unlikely to be related to treatment, and two cases of muscle weakness, deemed unrelated as they occurred weeks to months after the study treatment, and were thought to be related to tumor progression. In terms of clinical follow up, all patients have progressed at 1, 4, and 6 months, respectively. Overall survival times from date of infusion were 5, 15 and 10 months. DISCUSSION Direct delivery to brain tissue via CED remains a developing mode of therapeutic administration in the field of neuro-oncology. There are numerous examples now of successful administration of a wide variety of agents via a variety of new technologies that are designed for this purpose. Yet, questions remain as to how maximize the volume of target brain tissue that is treated during a session of CED, given the relatively low rates of infusion used by this approach (on the order of 1 to 20 m/m/m). Most notably, it has been long established that the relationship between the Vi and Vd depends upon the physical characteristics of the targeted tissue. For example, infusion into gray versus white matter is associated with a differential in Vd/Vi ratio[ 18 ]. Similarly, we previously showed that the Vd/Vi ratio was associated with whether the CED was performed in enhancing versus non-enhancing tumor tissue, due to the higher efflux rate observed in contrast enhancing tissue[ 14 ]. These findings have illustrated the need to overcome the relatively high efflux rate observed in enhancing tumor tissue if that is to be the target of treatment via CED. There are few options available to achieve that goal. One may be to use a larger therapeutic molecule that may be less likely to diffuse through a tumor’s defective BBB into the systemic circulation. However, larger molecules may not spread as far from the location of the infusing microcatheter, thereby limiting Vd. Another approach could be to increase the rate of infusion to provide additional driving force that can overcome what is assumed to be a fixed rate of efflux. The results of the current study appear to support this idea that tissues that may be subject to a relatively higher rate of efflux during CED can be more effectively treated by increasing the rate of infusion. In our prior report[ 14 ], we were limited to a rate of infusion of 0.825 m/m/m, and we found that there was very limited distribution of the infusate in enhancing tumor tissue. In this study, we explored using substantially higher rates of infusion within enhancing tumor, and not only did we observe more robust Vd within the enhancing tumor, we were also able to cover surrounding non-enhancing tumor tissue as well. This finding may provide support for a strategy of optimizing the placement of CED delivery catheters to treat both bulky (enhancing tumor) and infiltrative (non-enhancing tumor) disease with the smallest number of devices. Despite finding that we could more effectively treat enhancing tumor by increasing the rate of infusion, we did not cover the entire enhancing tumor target in these patients. In part, this may be as we limited treatment to a single CMC; had we placed 2 CMCs at opposing ends of the target volume, we likely would have covered all of the tumor and more surrounding tumor infiltrated brain. Also, we did not infuse at a rate higher than 20 m/m/m. While higher rates would likely produce greater Vd’s within the same infusion time period, there is an upper limit of rate that is defined by risk of infusate backflow around the delivery port, and by the risk of local tissue damage[ 19 , 20 ]. Finally, we limited this study to a 4-hour infusion as it was performed within the MRI environment only and with the patients under general anesthesia. Our previous report demonstrated that we could achieve higher Vd’s, in general, with infusions that continued for 48 to 96 hours in duration (with the patients awake in a neurosurgical step-down unit). Perhaps a longer infusion with the higher rate that we found to be safe would have more completely covered the enhancing tumor target with only one CMC. In patient #3, the rate of delivery was escalated rapidly but coverage was limited due to the proximity of the tumor to the ventricle, which resulted in leakage of the infusate into the ventricular space. CONCLUSIONS This study, which involved CED of topotecan along with Gd-DTPA into enhancing tumor tissue in the setting of recurrent high-grade glioma, showed that by increasing the rate of infusion we could obtain larger Vd’s within enhancing tumor tissue than has been shown previously with use of the same infusion device. This study provides support for further exploration of the relationship between infusion rate and target tissue coverage in order to optimize the pharmacokinetics of direct delivery of therapeutics to the brain. Declarations Competing Interests The study was funded by Infuseon Therapeutics, which is owned by the Cleveland Clinic. The Cleveland Multiport Catheter was licensed to Infuseon Therapeutics by the Cleveland Clinic. MAV is the inventor of the Cleveland Multiport Catheter and has patent royalty rights related to his former employment at the Cleveland Clinic. All remaining authors declare no conflict of interest. Author Contribution JKCL, NT, MV performed the procedure and contributed to data collectionCP, AP contributed to data collection, interpretation, and study organizationJKCL, MV wrote and edited the manuscript Data Availability Original data is provided within the supplementary information files References Theeler BJ, Gilbert MR (2015) Advances in the treatment of newly diagnosed glioblastoma. BMC Med 13: 293 doi:10.1186/s12916-015-0536-8 Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol 23: iii1-iii105 doi:10.1093/neuonc/noab200 Neth BJ, Webb MJ, Parney IF, Sener UT (2023) The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma. Pharmaceutics 15 doi:10.3390/pharmaceutics15041134 Daneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7: a020412 doi:10.1101/cshperspect.a020412 Steeg PS (2021) The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 18: 696-714 doi:10.1038/s41571-021-00529-6 Narsinh KH, Perez E, Haddad AF, Young JS, Savastano L, Villanueva-Meyer JE, Winkler E, de Groot J (2024) Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma. Curr Neurol Neurosci Rep 24: 123-139 doi:10.1007/s11910-024-01338-x Ter Linden E, Abels ER, van Solinge TS, Neefjes J, Broekman MLD (2024) Overcoming Barriers in Glioblastoma-Advances in Drug Delivery Strategies. Cells 13 doi:10.3390/cells13120998 Vogelbaum MA, Aghi MK (2015) Convection-enhanced delivery for the treatment of glioblastoma. Neuro Oncol 17 Suppl 2: ii3-ii8 doi:10.1093/neuonc/nou354 Kreatsoulas D, Damante M, Cua S, Lonser RR (2024) Adjuvant convection-enhanced delivery for the treatment of brain tumors. J Neurooncol 166: 243-255 doi:10.1007/s11060-023-04552-8 Vogelbaum MA (2005) Convection enhanced delivery for the treatment of malignant gliomas: symposium review. J Neurooncol 73: 57-69 doi:10.1007/s11060-004-2243-8 Vogelbaum MA (2007) Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review. J Neurooncol 83: 97-109 doi:10.1007/s11060-006-9308-9 Sampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodriguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK, Investigators PT (2010) Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 113: 301-309 doi:10.3171/2009.11.JNS091052 Mueller S, Polley MY, Lee B, Kunwar S, Pedain C, Wembacher-Schroder E, Mittermeyer S, Westphal M, Sampson JH, Vogelbaum MA, Croteau D, Chang SM (2011) Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study. J Neurooncol 101: 267-277 doi:10.1007/s11060-010-0255-0 Vogelbaum MA, Brewer C, Barnett GH, Mohammadi AM, Peereboom DM, Ahluwalia MS, Gao S (2018) 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: 1-10 doi:10.3171/2017.10.JNS171845 Anderson RC, Kennedy B, Yanes CL, Garvin J, Needle M, Canoll P, Feldstein NA, Bruce JN (2013) Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr 11: 289-295 doi:10.3171/2012.10.PEDS12142 Brady ML, Raghavan R, Singh D, Anand PJ, Fleisher AS, Mata J, Broaddus WC, Olbricht WL (2014) In vivo performance of a microfabricated catheter for intraparenchymal delivery. J Neurosci Methods 229: 76-83 doi:10.1016/j.jneumeth.2014.03.016 Han SJ, Bankiewicz K, Butowski NA, Larson PS, Aghi MK (2016) Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system. Expert Rev Neurother 16: 635-639 doi:10.1080/14737175.2016.1175939 Idema S, Caretti V, Lamfers ML, van Beusechem VW, Noske DP, Vandertop WP, Dirven CM (2011) Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain. PLoS One 6: e24396 doi:10.1371/journal.pone.0024396 Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, Berger MS, Bankiewicz K (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103: 923-929 doi:10.3171/jns.2005.103.5.0923 White E, Bienemann A, Malone J, Megraw L, Bunnun C, Wyatt M, Gill S (2011) An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery. J Neurosci Methods 199: 87-97 doi:10.1016/j.jneumeth.2011.04.027 Additional Declarations Competing interest reported. The study was funded by Infuseon Therapeutics, which is owned by the Cleveland Clinic. The Cleveland Multiport Catheter was licensed to Infuseon Therapeutics by the Cleveland Clinic. MAV is the inventor of the Cleveland Multiport Catheter and has patent royalty rights related to his former employment at the Cleveland Clinic. All remaining authors declare no conflict of interest. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5790058","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":409207614,"identity":"329cb51e-b2df-4493-8fe2-60bc68bd56ac","order_by":0,"name":"James K. C. 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C.","lastName":"Liu","suffix":""},{"id":409207617,"identity":"f2d05a90-d99c-4012-b9df-84050a19c234","order_by":1,"name":"Nam Tran","email":"","orcid":"","institution":"Moffitt Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Nam","middleName":"","lastName":"Tran","suffix":""},{"id":409207622,"identity":"97359560-7fa4-4565-81b1-d4016d19023b","order_by":2,"name":"Cecily Piteo","email":"","orcid":"","institution":"Moffitt Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Cecily","middleName":"","lastName":"Piteo","suffix":""},{"id":409207626,"identity":"d4e750ee-2a7d-40cb-af92-6aa8f5338ca5","order_by":3,"name":"Alisa Peinhardt","email":"","orcid":"","institution":"Moffitt Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Alisa","middleName":"","lastName":"Peinhardt","suffix":""},{"id":409207629,"identity":"15a8c953-9c1d-42c1-b96e-cdc293f2bf19","order_by":4,"name":"Michael A. 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T1 weighted MRI of patient 1 (a), patient 2(b), and patient 3 (c)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5790058/v1/5ce3efbd3646d29f32168987.png"},{"id":82177072,"identity":"5207bfb4-b308-4858-84fb-1e64af676739","added_by":"auto","created_at":"2025-05-07 11:16:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":947876,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5790058/v1/cc4d17b8-6573-4310-b375-4e72fc7f76a2.pdf"},{"id":75408333,"identity":"075b5c97-b688-4076-8557-979076f4018b","added_by":"auto","created_at":"2025-02-04 08:58:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1732021,"visible":true,"origin":"","legend":"","description":"","filename":"InfuseonSubject13data.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5790058/v1/31b27a3b0d96bb4a36cd0284.pdf"}],"financialInterests":"Competing interest reported. The study was funded by Infuseon Therapeutics, which is owned by the Cleveland Clinic. The Cleveland Multiport Catheter was licensed to Infuseon Therapeutics by the Cleveland Clinic. MAV is the inventor of the Cleveland Multiport Catheter and has patent royalty rights related to his former employment at the Cleveland Clinic. All remaining authors declare no conflict of interest.","formattedTitle":"Results of a Pilot Trial of Infusion Rate Escalation During Convection Enhanced Delivery of Topotecan with a Multiport Catheter","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eGlioblastoma (GBM), the most common primary malignant brain tumor, remains incurable with median survival rates generally less than 2 years, and a 5-year survival rate of less than 5% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Few therapies are approved by the FDA specifically for the treatment of newly-diagnosed GBM, and no FDA-approved treatment has shown the ability to extend survival in recurrent GBM (rGBM)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There are myriad reasons for the failure of multiple approaches to improving the outcome of patients with GBM including intra-tumoral genomic heterogeneity, tumor-induced systemic and local immunosuppression, and elevated expression of drug resistance pumps/DNA repair mechanisms. While these mechanisms of resistance may be shared with other cancers, GBM has a unique form of protection from therapy via the presence of blood-brain barrier (BBB) and blood-tumor barrier (BTB)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These barriers block most classes of therapeutics from accessing tumor cells at therapeutic concentrations when treatments are given by conventional routes of administration (oral or IV). Direct administration of therapeutics to the site of disease within the brain has emerged as an alternative route of therapeutic delivery[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. One of the most widely used approaches used for direct therapeutic delivery to the brain is convection enhanced delivery (CED)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe earliest clinical trials that involved the use of CED as a delivery mechanism failed to demonstrate clinical benefit; however, subsequent studies that included the use of tracers that could be imaged in real time indicated that a major source of failure related to the use of delivery catheters that did not have the proper technical design characteristics needed to ensure successful delivery via this mechanism[\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. More recent clinical trials performed with the use of CED-optimized technologies have demonstrated successful therapeutic delivery, confirmed with the use of a variety of imaging modalities[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. One such delivery technology is the Cleveland Multiport Catheter (CMC), which has been shown to successfully delivery a combination of topotecan and gadolinium-DTPA (gd-DTPA) in patients with recurrent GBM (rGBM)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In that study, there was a distinct difference in the volume of distribution (Vd) achieved with the rate and volume of infusion (Vi) specified in the protocol used in the study protocol when a CMC was placed into contrast enhancing (bulk) tumor versus non-contrast enhancing tumor infiltrated brain. This discrepancy reflected the fact that the efflux rate of enhancing tumor, where the \u0026ldquo;leaky\u0026rdquo; vascular system can rapidly carry away infusate thereby limiting its dispersion, is much higher than that of non-enhancing tumor, where the BBB remains intact thereby allowing for more uninterrupted infusate dispersion[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The protocol used for that study did not permit escalation of the infusion rate. To investigate whether we could safely and effectively treat enhancing tumor using higher infusion rates, we performed a rate escalation study using a single CMC.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis pilot trial was performed under the US Food and Drug Administration\u0026rsquo;s Investigational New Drug (IND) process (Sponsor-Investigator IND #117,240 issued to MAV). It was a single arm, prospective, open-label therapeutic trial approved by the Moffitt Cancer Center institutional review board and carried out in accordance with the Declaration of Helsinki. All patients signed a study-specific written informed consent, which included disclosure of the Sponsor-Investigator\u0026rsquo;s financial conflict of interest (the Sponsor-Investigator had an institutionally approved conflict of interest management plan in place, which was periodically audited by institutional personnel). All study procedures were carried out by financially non-conflicted site personnel. This study was registered at ClinicalTrials.gov on 25/4/2019 (NCT03927274).\u003c/p\u003e \u003cp\u003eThe primary objective of this study was to investigate, by MRI, the spatial and temporal distribution of topotecan with Gd-DTPA in enhancing tumor administered intra-operatively by CED via a single implanted CMC, and to investigate the influence of rate on the Vd. Secondary objectives included evaluation of the extent of backflow around the implanted catheter, assessment of safety, tolerability and toxicity of topotecan administered via CED, and evaluation of the activity of topotecan administered via CED to patients with rGBM.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003ePatients had to meet all of the following inclusion criteria: 1) pathologically confirmed WHO grade III or IV (high grade) glioma (HGG) that has undergone prior surgical biopsy or resection and treated with adjuvant chemoradiotherapy; 2) Imaging-based evidence of recurrence or progression with a plan to perform stereotactic biopsy for confirmation of recurrence/progression and no requirement for surgical resection to relieve clinically-significant mass effect; 3) age\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;18 years; 4) Karnofsky Performance Status of 70\u0026ndash;100; laboratory values that were permissible for a cranial neurosurgical procedure. Key exclusion criteria included diffuse subependymal or CSF disease; tumors involving the posterior fossa or both hemispheres; positive pregnancy test in females; radiation or chemotherapy treatment within 4 weeks of study enrollment; active infection; or inability to undergo magnetic resonance imaging.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInvestigational Procedures\u003c/h3\u003e\n\u003cp\u003eA clinically indicated stereotactic biopsy was performed under general endotracheal anesthesia (GETA) with use of a frameless image guidance surgical navigation system (Brainlab, Germany). A frozen section was evaluated by a board certified neuropathologist, and when the diagnosis of recurrent HGG was determined, one CMC catheter primed with gd-DTPA (5 mM) was stereotactically placed via the same burr hole as the biopsy and secured in place as described in a prior report (Fig.\u0026nbsp;1)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. While under GETA, the patients were then taken to an adjacent MRI suite. A baseline scan was obtained and then each of the 4 microcatheters of the CMC was attached, with use of sterile technique, to an infusion line pre-primed with the investigational solution (topotecan (0.05 mg/mL) mixed with gd-DTPA (5 mM)) connected to a 10 cc syringe mounted in a Medfusion 3500 syringe pump. The initial rate of infusion for the first patient was 5 microliters/minute/microcatheter and the protocol permitted rate increases as directed by the investigator team after review of the distribution of gd-DTPA visualized on intermittent non-contrast MRIs that were performed approximately every 30 minutes. A magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence was used to provide visualization of the infused contrast agent on 1mm volumetrically acquired image slices. The infusions were continued until either the bulk (enhancing) tumor was fully covered by the infusion, or 4 hours of infusion time was reached; whichever was earliest. Each subsequent patient\u0026rsquo;s infusions were started at a rate of 5 microliters/minute/microcatheter higher than the previous patient, so long as backflow had not been observed at that rate in previous patients.\u003c/p\u003e \u003cp\u003eEvaluation of the primary endpoint (Vd of the co-infused gd-DTPA and % coverage of the enhancing tumor volume) was performed with the use of Brainlab iPlan. The Vd of gd-DTPA was used as a surrogate for topotecan distribution. Safety was evaluated with the use of CTCAE v.4.0 and causality was determined by investigators who did not have financial conflicts (JKCL, NT and CP). Original data is provided within the supplementary information files.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;1\u003c/b\u003e Cleveland Multiport catheter following intracranial placement through a single burr hole\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThree patients were treated under this pilot protocol between June, 2019 and February, 2023. The trial was closed in 2023 as the sponsor suspended operations. Demographic data for the patients is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Each of the patients had a recurrent glioblastoma that had been treated previously with surgical resection, standard dose external beam photon radiotherapy, and temozolomide chemotherapy. The target tumor volumes ranged from 1.4 to 4.65 cc, and a single CMC was placed in each case. Infusion data are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For patient 1, the initial infusion rate was 5 microliters per minute per microcatheter (m/m/m), and the maximum rate used was 15 m/m/m. The total volume of infusion (Vi) for the 4 microcatheters was 9.9 cc and the resulting volume of distribution (Vd), as measured by the volume of infused Gd-DTPA signal was 12.8 cc for a Vd/Vi ratio of 1.3. While there was coverage of both enhancing tumor and surrounding tumor infiltrated brain, the pattern of distribution was inhomogeneous and only 56% of the enhancing tumor was covered.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGBM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGBM\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMGMT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eunmethylated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnmethylated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor Location\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLeft temporal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRight parietal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLeft temporal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInfusion data\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTumor Volume\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDistributed Volume (Vd)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInfused Volume (Vi)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVd/Vi\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTarget Coverage Volume\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e% Target Coverage\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e56%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e79%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient 3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.366\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor patient 2, the initial rate started at 10 m/m/m and the maximum rate was 20 m/m/m. The total Vi remained at 9.9 cc and the Vd was 12.0 cc for a Vd/Vi ratio of 1.2. In this case, 79% of the enhancing tumor was covered, along with surrounding non-enhancing tumor infiltrated brain. Patient 3\u0026rsquo;s infusion started at 5 m/m/m and the maximum rate was 20 m/m/m. Unfortunately, there was extensive flow into the lateral ventricle and into the subarachnoid space from 2 of the microcatheters, which reflected a less-than-ideal catheter placement. Only 49% of the target enhancing tumor was covered and the Vd/Vi ratio was 0.7. \u003cb\u003eFigure 2\u003c/b\u003e shows examples of the maximal coverage obtained from each of the infusions.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;2\u003c/b\u003e Final infusion imaging. T1 weighted MRI of patient 1 (a), patient 2(b), and patient 3 (c)\u003c/p\u003e \u003cp\u003eAll of the infusions were well tolerated. There were a total of 35 adverse events (AEs) in the 3 patients, of which 19 were deemed unrelated to the drug or device by the treating physician. Of the other AEs, there were 3 grade 1 and one grade 2 AEs deemed possibly related to the study treatment, all of which recovered without intervention. There were three grade 3 AEs, two of which were in one patient. These consisted of one case of leukocystosis, deemed unlikely to be related to treatment, and two cases of muscle weakness, deemed unrelated as they occurred weeks to months after the study treatment, and were thought to be related to tumor progression.\u003c/p\u003e \u003cp\u003eIn terms of clinical follow up, all patients have progressed at 1, 4, and 6 months, respectively. Overall survival times from date of infusion were 5, 15 and 10 months.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eDirect delivery to brain tissue via CED remains a developing mode of therapeutic administration in the field of neuro-oncology. There are numerous examples now of successful administration of a wide variety of agents via a variety of new technologies that are designed for this purpose. Yet, questions remain as to how maximize the volume of target brain tissue that is treated during a session of CED, given the relatively low rates of infusion used by this approach (on the order of 1 to 20 m/m/m). Most notably, it has been long established that the relationship between the Vi and Vd depends upon the physical characteristics of the targeted tissue. For example, infusion into gray versus white matter is associated with a differential in Vd/Vi ratio[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Similarly, we previously showed that the Vd/Vi ratio was associated with whether the CED was performed in enhancing versus non-enhancing tumor tissue, due to the higher efflux rate observed in contrast enhancing tissue[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings have illustrated the need to overcome the relatively high efflux rate observed in enhancing tumor tissue if that is to be the target of treatment via CED. There are few options available to achieve that goal. One may be to use a larger therapeutic molecule that may be less likely to diffuse through a tumor\u0026rsquo;s defective BBB into the systemic circulation. However, larger molecules may not spread as far from the location of the infusing microcatheter, thereby limiting Vd. Another approach could be to increase the rate of infusion to provide additional driving force that can overcome what is assumed to be a fixed rate of efflux. The results of the current study appear to support this idea that tissues that may be subject to a relatively higher rate of efflux during CED can be more effectively treated by increasing the rate of infusion. In our prior report[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], we were limited to a rate of infusion of 0.825 m/m/m, and we found that there was very limited distribution of the infusate in enhancing tumor tissue. In this study, we explored using substantially higher rates of infusion within enhancing tumor, and not only did we observe more robust Vd within the enhancing tumor, we were also able to cover surrounding non-enhancing tumor tissue as well. This finding may provide support for a strategy of optimizing the placement of CED delivery catheters to treat both bulky (enhancing tumor) and infiltrative (non-enhancing tumor) disease with the smallest number of devices.\u003c/p\u003e \u003cp\u003eDespite finding that we could more effectively treat enhancing tumor by increasing the rate of infusion, we did not cover the entire enhancing tumor target in these patients. In part, this may be as we limited treatment to a single CMC; had we placed 2 CMCs at opposing ends of the target volume, we likely would have covered all of the tumor and more surrounding tumor infiltrated brain. Also, we did not infuse at a rate higher than 20 m/m/m. While higher rates would likely produce greater Vd\u0026rsquo;s within the same infusion time period, there is an upper limit of rate that is defined by risk of infusate backflow around the delivery port, and by the risk of local tissue damage[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Finally, we limited this study to a 4-hour infusion as it was performed within the MRI environment only and with the patients under general anesthesia. Our previous report demonstrated that we could achieve higher Vd\u0026rsquo;s, in general, with infusions that continued for 48 to 96 hours in duration (with the patients awake in a neurosurgical step-down unit). Perhaps a longer infusion with the higher rate that we found to be safe would have more completely covered the enhancing tumor target with only one CMC. In patient #3, the rate of delivery was escalated rapidly but coverage was limited due to the proximity of the tumor to the ventricle, which resulted in leakage of the infusate into the ventricular space.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis study, which involved CED of topotecan along with Gd-DTPA into enhancing tumor tissue in the setting of recurrent high-grade glioma, showed that by increasing the rate of infusion we could obtain larger Vd\u0026rsquo;s within enhancing tumor tissue than has been shown previously with use of the same infusion device. \u0026nbsp; This study provides support for further exploration of the relationship between infusion rate and target tissue coverage in order to optimize the pharmacokinetics of direct delivery of therapeutics to the brain.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003cp\u003eThe study was funded by Infuseon Therapeutics, which is owned by the Cleveland Clinic. The Cleveland Multiport Catheter was licensed to Infuseon Therapeutics by the Cleveland Clinic. MAV is the inventor of the Cleveland Multiport Catheter and has patent royalty rights related to his former employment at the Cleveland Clinic. All remaining authors declare no conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJKCL, NT, MV performed the procedure and contributed to data collectionCP, AP contributed to data collection, interpretation, and study organizationJKCL, MV wrote and edited the manuscript\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eOriginal data is provided within the supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTheeler BJ, Gilbert MR (2015) Advances in the treatment of newly diagnosed glioblastoma. BMC Med 13: 293 doi:10.1186/s12916-015-0536-8\u003c/li\u003e\n\u003cli\u003eOstrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol 23: iii1-iii105 doi:10.1093/neuonc/noab200\u003c/li\u003e\n\u003cli\u003eNeth BJ, Webb MJ, Parney IF, Sener UT (2023) The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma. Pharmaceutics 15 doi:10.3390/pharmaceutics15041134\u003c/li\u003e\n\u003cli\u003eDaneman R, Prat A (2015) The blood-brain barrier. Cold Spring Harb Perspect Biol 7: a020412 doi:10.1101/cshperspect.a020412\u003c/li\u003e\n\u003cli\u003eSteeg PS (2021) The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 18: 696-714 doi:10.1038/s41571-021-00529-6\u003c/li\u003e\n\u003cli\u003eNarsinh KH, Perez E, Haddad AF, Young JS, Savastano L, Villanueva-Meyer JE, Winkler E, de Groot J (2024) Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma. Curr Neurol Neurosci Rep 24: 123-139 doi:10.1007/s11910-024-01338-x\u003c/li\u003e\n\u003cli\u003eTer Linden E, Abels ER, van Solinge TS, Neefjes J, Broekman MLD (2024) Overcoming Barriers in Glioblastoma-Advances in Drug Delivery Strategies. Cells 13 doi:10.3390/cells13120998\u003c/li\u003e\n\u003cli\u003eVogelbaum MA, Aghi MK (2015) Convection-enhanced delivery for the treatment of glioblastoma. Neuro Oncol 17 Suppl 2: ii3-ii8 doi:10.1093/neuonc/nou354\u003c/li\u003e\n\u003cli\u003eKreatsoulas D, Damante M, Cua S, Lonser RR (2024) Adjuvant convection-enhanced delivery for the treatment of brain tumors. J Neurooncol 166: 243-255 doi:10.1007/s11060-023-04552-8\u003c/li\u003e\n\u003cli\u003eVogelbaum MA (2005) Convection enhanced delivery for the treatment of malignant gliomas: symposium review. J Neurooncol 73: 57-69 doi:10.1007/s11060-004-2243-8\u003c/li\u003e\n\u003cli\u003eVogelbaum MA (2007) Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review. J Neurooncol 83: 97-109 doi:10.1007/s11060-006-9308-9\u003c/li\u003e\n\u003cli\u003eSampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodriguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK, Investigators PT (2010) Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 113: 301-309 doi:10.3171/2009.11.JNS091052\u003c/li\u003e\n\u003cli\u003eMueller S, Polley MY, Lee B, Kunwar S, Pedain C, Wembacher-Schroder E, Mittermeyer S, Westphal M, Sampson JH, Vogelbaum MA, Croteau D, Chang SM (2011) Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study. J Neurooncol 101: 267-277 doi:10.1007/s11060-010-0255-0\u003c/li\u003e\n\u003cli\u003eVogelbaum MA, Brewer C, Barnett GH, Mohammadi AM, Peereboom DM, Ahluwalia MS, Gao S (2018) 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: 1-10 doi:10.3171/2017.10.JNS171845\u003c/li\u003e\n\u003cli\u003eAnderson RC, Kennedy B, Yanes CL, Garvin J, Needle M, Canoll P, Feldstein NA, Bruce JN (2013) Convection-enhanced delivery of topotecan into diffuse intrinsic brainstem tumors in children. J Neurosurg Pediatr 11: 289-295 doi:10.3171/2012.10.PEDS12142\u003c/li\u003e\n\u003cli\u003eBrady ML, Raghavan R, Singh D, Anand PJ, Fleisher AS, Mata J, Broaddus WC, Olbricht WL (2014) In vivo performance of a microfabricated catheter for intraparenchymal delivery. J Neurosci Methods 229: 76-83 doi:10.1016/j.jneumeth.2014.03.016\u003c/li\u003e\n\u003cli\u003eHan SJ, Bankiewicz K, Butowski NA, Larson PS, Aghi MK (2016) Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system. Expert Rev Neurother 16: 635-639 doi:10.1080/14737175.2016.1175939\u003c/li\u003e\n\u003cli\u003eIdema S, Caretti V, Lamfers ML, van Beusechem VW, Noske DP, Vandertop WP, Dirven CM (2011) Anatomical differences determine distribution of adenovirus after convection-enhanced delivery to the rat brain. PLoS One 6: e24396 doi:10.1371/journal.pone.0024396\u003c/li\u003e\n\u003cli\u003eKrauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, Berger MS, Bankiewicz K (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103: 923-929 doi:10.3171/jns.2005.103.5.0923\u003c/li\u003e\n\u003cli\u003eWhite E, Bienemann A, Malone J, Megraw L, Bunnun C, Wyatt M, Gill S (2011) An evaluation of the relationships between catheter design and tissue mechanics in achieving high-flow convection-enhanced delivery. J Neurosci Methods 199: 87-97 doi:10.1016/j.jneumeth.2011.04.027\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Glioblastoma, Convection Enhanced Delivery, Clinical Trial, Surgical Innovation","lastPublishedDoi":"10.21203/rs.3.rs-5790058/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5790058/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e Volume of distribution (Vd) during convection enhanced delivery is impacted by the physical characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A single center, IRB-approved pilot study was conducted to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent high-grade glioma. A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Three patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events. The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIncreasing the rate of infusion can allow for larger volume of distribution into enhancing tumor tissue.\u003c/p\u003e","manuscriptTitle":"Results of a Pilot Trial of Infusion Rate Escalation During Convection Enhanced Delivery of Topotecan with a Multiport Catheter","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-04 08:58:26","doi":"10.21203/rs.3.rs-5790058/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ff7762ba-5b5b-4aac-b2aa-5f1870d14fcf","owner":[],"postedDate":"February 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43636293,"name":"Health sciences/Neurology/Neurological disorders/Cns cancer"},{"id":43636294,"name":"Health sciences/Oncology/Surgical oncology"}],"tags":[],"updatedAt":"2025-05-07T11:08:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-04 08:58:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5790058","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5790058","identity":"rs-5790058","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}