Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>In this clinical trial report, the authors analyze safety and infusion distribution of IL13-<jats:italic>Pseudomonas</jats:italic> exotoxin, an antitumor chimeric molecule, administered via intratumoral convection enhanced delivery (CED) in pediatric patients with diffuse intrinsic pontine glioma (DIPG).</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>This was a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via single-catheter CED into 5 pediatric DIPG patients. IL13-PE38QQR was administered to regions of tumor selected by radiographic findings. Two escalating dose levels were evaluated: 0.125 µg/mL in cohort 1 and 0.25 µg/mL in cohort 2. Real-time MRI was performed during intratumoral infusions, and MRI and MR spectroscopy were performed before and after the infusions. Clinical evaluations, including parent-reported quality of life (QOL), were assessed at baseline and 4 weeks post-infusion.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Direct infusion of brainstem tumor with IL13-PE using the CED technique in patients with DIPG produced temporary arrest of disease progression in 2 of 5 patients, both of whom subsequently received a second infusion. All 5 patients showed signs of disease progression by 12 weeks after initial infusion. Two patients experienced transient cranial nerve deficits and lethargy after infusion, and these deficits resolved with corticosteroid treatment in both cases. No patient had radiographic evidence of acute or long-term treatment toxicity. Parent-reported QOL was consistent with medical outcomes.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Even though IL13-PE delivered by CED did not reach the entire MRI-defined tumor volume in any patient, short-term radiographic antitumor effects were observed in 2 of the 5 patients treated. The patients’ performance status did not improve. Drug delivery using multiple catheters may produce improved outcomes.</jats:p><jats:p>Clinical trial registration no.: NCT00088061 (clinicaltrials.gov)</jats:p></jats:sec>

Evaluating infusate parameters for direct drug delivery to the brainstem: a comparative study of convection-enhanced delivery versus osmotic pump delivery

“…For example, whereas we used a delivery rate of 1 μl/min, clinically, delivery rates in patients with DIPG have been reported in the range of 5-10 μl/min. 9 Despite this, we believe the trends we report are likely to persist in patients with DIPG, although the most optimal delivery value can only truly be optimized prospectively in a clinical trial.…”

“…3 Interstitial infusion by CED to the brainstem has been proven safe and feasible in multiple animal models, and recently a phase I clinical trial in children with DIPG validated this as safe in human patients. 9,17,19,23,28,31 Post hoc analyses after CED have demonstrated that therapeutic agents achieve high concentrations in the regional parenchyma and adjacent white matter tracts, with negligible efflux in the presence of an intact BBB. 6,7,22,32 Other interstitial infusion approaches distribute infusate by other mechanisms, including osmotic pump delivery, which relies solely on osmotic gradients after catheter insertion to encourage distribution within the target tissue.…”

Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology

“…Therefore, the understanding acquired from adults was applied to children suffering from the disease. However, although treatments for high-grade glioma have achieved modest improvements in survival rates in adults, in children these treatments did not make any difference [ 103 , 104 ]. In 2012, two groups—Schwartzentruber et al and Lindroth et al—showed that mutations in genes that encode histones, the spool-like proteins around which DNA is wound, contribute to high-grade glioma [ 105 , 106 ].…”

The intersect of neurosurgery with diffuse intrinsic pontine glioma

“…14 Clinical trials would soon follow that aimed to more concretely assess safety and define infusion parameters by using a systematic dose-escalation format. 4,6,30 Our group was able to report comprehensively that CED in the brainstem of children with DIPG is a rational and reasonably safe treatment option. Twenty-eight patients were enrolled into a phase 1 clinical trial (registration no.…”