Repeat convection-enhanced delivery for diffuse intrinsic pontine glioma

Abstract

OBJECTIVEWhile the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma.METHODSPatients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software.RESULTSSeven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45).CONCLUSIONSThis series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.

Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma

“…Moving an IL13Rα2 ADC to clinical use will require optimizing the antibody binding dynamics and maximizing efficacy of the cytotoxic payload while minimizing peripheral toxicity, optimizations which are the requisite next steps for initiation of an anti-IL13Rα2 ADC clinical trial for DIPG. Fortunately, convection-enhanced delivery (CED) of an antibody is already known to be clinically feasible[ 3 ]. Overall, despite the potential limitations of PBD as the cytotoxic payload, anti-IL13Rα2 ADC agents show promise as a therapeutic strategy for an exceptionally intractable disease such as DIPG.…”

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

“…Several other clinical trials are building upon the studies mentioned previously [ 10 , 72 , 75 ]. An ongoing clinical trial (NCT01502917) continues to investigate the intratumoral binding ability and tumor growth suppression of [ 124 I]-8H9 delivered by CED to the brainstem tumor with repeated CED infusions in pediatric patients [ 80 ]. Another clinical trial is investigating the safety and efficacy of CED-infused panobinostat for H3K27M-mutant tumor suppression (NCT03566199).…”

An Update on Gene Therapy Approaches for Parkinson’s Disease: Restoration of Dopaminergic Function

“…2 ). This CED platform has now proven safe in intracranial drug delivery in multiple clinical trials with follow-up, including gene therapy trials of AAV2-hAADC for PD, AAV2-GDNF for PD, and AAV2-hAADC for AADC deficiency [ 8, 9, 31, 38 ], and brain tumor drug delivery trials [ 39–43 ].…”