Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial

Abstract

Background: Topotecan is cytotoxic to glioma cells but is clinically ineffective because of drug delivery limitations. Systemic delivery is limited by toxicity and insufficient brain penetrance, and, to date, convection-enhanced delivery (CED) has been restricted to a single treatment of restricted duration. To address this problem, we engineered a subcutaneously implanted catheter-pump system capable of repeated, chronic (prolonged, pulsatile) CED of topotecan into the brain and tested its safety and biological effects in patients with recurrent glioblastoma.

Methods: We did a single-centre, open-label, single-arm, phase 1b clinical trial at Columbia University Irving Medical Center (New York, NY, USA). Eligible patients were at least 18 years of age with solitary, histologically confirmed recurrent glioblastoma showing radiographic progression after surgery, radiotherapy, and chemotherapy, and a Karnofsky Performance Status of at least 70. Five patients had catheters stereotactically implanted into the glioma-infiltrated peritumoural brain and connected to subcutaneously implanted pumps that infused 146 μM topotecan 200 μL/h for 48 h, followed by a 5-7-day washout period before the next infusion, with four total infusions. After the fourth infusion, the pump was removed and the tumour was resected. The primary endpoint of the study was safety of the treatment regimen as defined by presence of serious adverse events. Analyses were done in all treated patients. The trial is closed, and is registered with ClinicalTrials.gov, NCT03154996.

Findings: Between Jan 22, 2018, and July 8, 2019, chronic CED of topotecan was successfully completed safely in all five patients, and was well tolerated without substantial complications. The only grade 3 adverse event related to treatment was intraoperative supplemental motor area syndrome (one [20%] of five patients in the treatment group), and there were no grade 4 adverse events. Other serious adverse events were related to surgical resection and not the study treatment. Median follow-up was 12 months (IQR 10-17) from pump explant. Post-treatment tissue analysis showed that topotecan significantly reduced proliferating tumour cells in all five patients.

Interpretation: In this small patient cohort, we showed that chronic CED of topotecan is a potentially safe and active therapy for recurrent glioblastoma. Our analysis provided a unique tissue-based assessment of treatment response without the need for large patient numbers. This novel delivery of topotecan overcomes limitations in delivery and treatment response assessment for patients with glioblastoma and could be applicable for other anti-glioma drugs or other CNS diseases. Further studies are warranted to determine the effect of this drug delivery approach on clinical outcomes.

Funding: US National Institutes of Health, The William Rhodes and Louise Tilzer Rhodes Center for Glioblastoma, the Michael Weiner Glioblastoma Research Into Treatment Fund, the Gary and Yael Fegel Foundation, and The Khatib Foundation.

Figure 1:. Chronic CED of TPT achieves large and stable volumes of distribution

A: Each patient was infused over the course of 48 hours followed by a 5–7 day washout period before the next infusion. All five patients showed large changes in volume of distribution. B: The estimated volume of distribution of the infused contrast was plotted as a function of time and fit to a gamma function for each patient. The solid black line represents the mean time course across subjects, which peaked at 43.1 hours with a mean volume of 20.4 mL.

Figure 2:. Chronic CED of TPT targets proliferating tumor populations and shifts tumor phenotype

A-B: Violin plot displaying quantification of SOX2 (glioma marker) and Ki67 (proliferation marker) by labeling index across all MRI-localized biopsies from all patients, comparing biopsies taken pre- and post-CED using a student’s T-test (n=86). C: PET scans were performed on the last 3 patients in this series. The difference between post- and pre-infusion PET images were computed and converted to percent signal change. The white outline represents the maximum infused volume; the yellow outline represents the control hemisphere. Blue voxels represent decreases in metabolism, red voxels represent increases in metabolism, and gray voxels represent no change after treatment. D: All three patients showed a large (6.2–17.2%) reduction in metabolism within the infused volume mask. E: The regions treated with TPT demonstrated reduced Ki67 labeling and reduced ¹⁸FDG metabolism (n = 14). These two measures were exponentially related, such that, the larger the reduction in metabolism, the lower the proliferation index.