Cleveland Multiport Catheter Enhances Topotecan Delivery in High-Grade Glioma

Report from first-in-human study of new convection-enhanced delivery device

The Cleveland Multiport Catheter (CMC), a novel four-port device for convection-enhanced delivery, successfully conveys high volumes of chemotherapy to enhancing and nonenhancing regions of recurrent high-grade gliomas. So conclude Cleveland Clinic researchers who presented results from a clinical trial in the first 12 patients treated with the device at the 2017 annual meeting of the Society for Neuro-Oncology in San Francisco.

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“Breaking through the blood-brain barrier is a continuing major challenge for delivering therapeutic drugs to fight brain cancers,” says Cleveland Clinic neurosurgeon Michael A. Vogelbaum, MD, PhD, the study’s lead investigator. “We are very encouraged to see that our catheter can effectively deliver around the blood-brain barrier in the setting of both solid and infiltrative brain tumors.”

Dr. Vogelbaum is Associate Director of the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center and Director of the Center for Translational Therapeutics and Professor of Surgery at Cleveland Clinic Lerner College of Medicine. He is one of the inventors of the CMC and leads the Cleveland Clinic team testing the device. He is founder and chief medical officer of Infuseon Therapeutics Inc., a Cleveland Clinic-owned spinoff company that is funding clinical development of the CMC. Dr. Vogelbaum’s roles in this development effort are covered under a Cleveland Clinic-approved conflict-of-interest management plan.

The CMC backstory

The CMC was granted FDA clearance in March 2017 as a therapeutic delivery device. While convection-enhanced delivery (CED) has been in investigational use for about 20 years, no drug has yet received FDA approval for direct delivery into the brain parenchyma.

The CMC, developed at Cleveland Clinic in partnership with Cleveland-based multinational manufacturer Parker Hannifin Corp., has several advantages over similar devices under investigation for CED:

  • While other devices have a single drug delivery catheter, the CMC has four microcatheters equally spaced around the tip of the CMC shaft through which drug can be delivered (see image at top of post), requiring fewer devices to cover a large volume of tissue.
  • The CMC can be placed in an operating room equipped with conventional neurosurgical guidance technology, avoiding the intraoperative MRI capabilities required by other delivery devices.
  • The CMC can be left in place for days (versus several hours for most other delivery devices), allowing delivery of more drug.

The CMC is surgically implanted and connected to low-rate infusion pumps. More details about the CMC are in this previous Consult QD post.

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Study methods and findings

This study focused on recurrent high-grade glioma, a brain cancer that not only forms solid (enhancing) tumors but also grows in the brain in a highly infiltrative manner (nonenhancing), making it particularly resistant to radiation therapy and surgical excision. The study involved two pilot trials:

  • Drug delivery was evaluated in both enhancing tumor and tumor-infiltrated brain (3 patients).
  • Drug delivery was evaluated in tumor-infiltrated brain after resection of the enhancing tumor (9 patients).

In both trials, two agents were delivered simultaneously through the CMC:

  • Topotecan, a standard chemotherapeutic agent used to treat lung and colon cancers. Although topotecan has demonstrated effectiveness against glioma in cell cultures, it cannot cross the blood-brain barrier under conventional delivery methods and consequently has not been effective when given by its conventional intravenous route of delivery.
  • A gadolinium tracer (gadolinium DTPA) visible on MRI. It was used to detect distribution and thereby evaluate the efficacy of drug delivery.

All 12 patients underwent successful placement of two CMCs each and completed infusions ranging from 48 to 96 hours. All catheters were placed with conventional operating room technology. MRI was performed intermittently during infusion.

Large differences were found in the volumes of distribution based on the site of delivery, with the highest volumes delivered to tumor-infiltrated regions (25-92 mL). No obvious backflow into the CMC shaft was observed intra- or perioperatively. No hemorrhages occurred during catheter placement or removal.

Next steps

Dr. Vogelbaum’s team is currently recruiting patients for a third trial that will focus on optimizing the use of the CMC to deliver to the enhancing (solid) portion of recurrent tumors. They are also developing additional new devices for both short- and long-term delivery of therapeutics to the brain.

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The CMC is not limited to delivery of chemotherapies. It is designed to be capable of delivering other biologic and cellular therapies to the brain, for brain tumors and also for other neurological conditions such as Alzheimer’s disease, Parkinson’s disease and epilepsy.

Dr. Vogelbaum notes that the CMC also could potentially be used to deliver therapeutics to solid tumors elsewhere in the body. Localized delivery could potentially avoid complications such as the bone marrow toxicity seen with typical systemic administration of many chemotherapies.

“The CMC has demonstrated excellent promise in our initial trials,” he says. “Successful localized and locoregional delivery is critical to treating brain tumors and a multitude of other conditions as well.”