Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies

Department of Neurosurgery, University of California, San Francisco, California 94143-0350, USA.
Neurosurgical FOCUS (Impact Factor: 2.11). 02/2006; 20(4):E15.
Source: PubMed


Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells.
Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively.
The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

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    • "The trial failed to achieve its objective of superiority over Gliadel Wafer due to non-selective patients based on IL-13 receptor expression, catheter positioning, and poor drug distribution. The clinical toxicity of IL13-PE38QQR was likely because of non-selective binding of the toxin to the IL13Rα1/IL-4α type II receptor1516171819. Rather than targeting the IL-13 receptor with a toxin, we have taken an alternative approach to specifically inhibit the expression of IL13Rα2 by using short hairpin RNA (shRNA). "
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    • "bacterial toxins genetically fused to targeted derivatives of IL-13 to eradicate IL-13Rα2–expressing tumors. Importantly, a first generation IL-13– based cytotoxin, IL-13–PE38QQR, has shown clinical activity in phase 1 and 2 clinical trials for GBM patients when administered locally with convection-enhanced delivery (CED) [21] [22] [23] [24] [25] [26]. Of significance, the phase 3 Randomized Evaluation of CED of IL-13–PE38QQR with Survival End points (PRECISE) trial demonstrated increased overall survival of patients treated by neurosurgeons with experience performing CED [27], although it did not reach its clinical end points owing to a number of factors, including use of early generation suboptimized CED, lack of biomarker expression screening, and possibly affinity toward the physiologically abundant IL-13Rα1/IL4Rα heterodimer that is expressed on healthy brain [27] [28] [29]. "
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