NCT06666712

Chronic CED of TPT for Recurrent Malignant Glioma

Chronic Convection Enhanced Delivery of Topotecan for Recurrent Malignant Glioma

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 6 (estimated)
• Sponsor: Jeffrey N. Bruce · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The primary goal of this study is to establish the safety of chronic Convection Enhanced Delivery (CED) of the chemotherapeutic drug Topotecan for patients with recurrent malignant glioma that harbors the Isocitrate Dehydrogenase mutation (IDH-mut). The secondary goal of the study is to study drug distribution and assess the tumor response to prolonged continuous CED of Topotecan. Convection Enhanced Delivery is a novel method of drug delivery that allows administration of a drug directly to the brain. In CED, a drug pump is placed under the skin in the chest or abdominal region. The pump is connected to a catheter that is tunneled underneath the skin to the brain. The tip of the catheter then infuses Topotecan directly onto the brain tumor. There will be a total of four treatment infusions over the course of 23-29 days, with a 5-7-day rest period between each infusion. Throughout this period, patients' health will be monitored through imaging, blood draws, and regular exams. At the end of the treatment period, the pump will be removed, followed by resection of the tumor. Patients will be followed for the duration of their lives. This is the investigator's second clinical trial studying CED of TPT in recurrent glioma. In the prior Phase 1b trial, chronic pulsatile CED safely and effectively delivered Topotecan to patients with IDH mutant recurrent Glioblastoma (WHO grade 4).

Detailed description

Malignant gliomas are among the most pernicious of human tumors. They are locally invasive and universally recurrent, often recurring within two centimeters of the original resection cavity. Although numerous chemotherapeutic drugs demonstrate significant anti-tumor activity in preclinical studies, their efficacy in clinical trials has been dismal; systemic delivery fails to achieve therapeutic drug levels in tumor cells due to various factors including limited blood-brain barrier permeability and systemic toxicity. Convection-Enhanced Delivery (CED) can circumvent this challenge by delivering therapeutics directly to the brain, bypassing systemic circulation and the blood-brain barrier. CED uses a subcutaneously implanted catheter-pump system, enabling sustained, prolonged delivery while foregoing the need for an external catheter and bedside pump. In the most recent Phase Ib clinical trial, chronic pulsatile CED safely and effectively delivered Topotecan (TPT), a topoisomerase I inhibitor, to patients with recurrent Glioblastoma (WHO grade 4), Isocitrate Dehydrogenase wild type (IDH-WT). However, malignant glioma displays marked genetic and phenotypic heterogeneity not fully reflected by IDH-WT glioblastoma. In the current study, the investigators aim to further demonstrate the safety and efficacy of this drug delivery system in IDH mutated malignant glioma. The investigators hypothesize that extended chronic pulsatile local-regional delivery of TPT continues to be safe, effective, and feasible in patients with recurrent IDH mutated WHO grade 3-4 malignant glioma. This study will use the previously established method of CED through subcutaneously implanted pumps combined with non-invasive imaging to monitor drug distribution. As in the previous study, the drug's distribution will be characterized using an innovative, non-invasive methodology for measuring intracerebral distribution. The hypothesis is that intracerebral CED can safely, effectively, and chronically administer TPT to patients with recurrent malignant glioma, including WHO grade 3-4 IDH1/2 mutated subtypes, and drug distribution can be measured non-invasively. The inclusion of IDH1/2 mutated glioma (WHO grade 3-4) marks an expansion from our prior Phase Ib trial to better reflect the heterogeneity of malignant glioma. The chronic CED and non-invasive imaging methodology was developed in the porcine model and was subsequently shown to be safe for patients with recurrent WHO grade 4 glioma in the phase Ib clinical trial. Similar to the previous trial design, patients will undergo implantation of the CED catheters and subcutaneously implanted pumps, after which four cycles of TPT/gadolinium will be administered. Each cycle will include 48 hours of active drug infusion followed by five to seven days of drug holiday. Following the four cycles, the catheters and pumps will be removed and tumors will be resected. Tumoral and parenchymal distribution of gadolinium (measured by MRI) will be correlated with TPT levels (measured by mass spectrophotometry) in tissue samples obtained upon tumor resection. Cytotoxic response to TPT will be investigated by both MRI and direct histologic comparison between tissue samples taken at resection versus initial biopsy and MRI. At the conclusion of these studies, the investigators expect to demonstrate the safe and successful delivery of chronic, high doses of TPT directly into patients' tumors, thereby avoiding the limitations imposed by conventional systemic delivery.

Conditions

• Brain Tumor, Recurrent
• Malignant Glioma (WHO Grade III or IV)
• IDH1/IDH2 Mutation

Interventions

Type	Name	Description
DRUG	Topotecan	Topotecan (TPT) is a chemotherapeutic agent that is a topoisomerase inhibitor. This intervention is uniquely distinguished through its administration using an externalized catheter and external microinfusion pump (Convection-Enhanced Delivery)

Timeline

• Start date: 2026-05-01
• Primary completion: 2028-01-01
• Completion: 2028-01-01
• First posted: 2024-10-31
• Last updated: 2026-04-15

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study