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

Sandeep Kunwar, Susan M. Chang, Michael D. Prados, Mitchel S. Berger, John H. Sampson, David Croteau, Jeffrey Sherman, Amy Y. Grahn, Vince S. Shu, Jeanne L. Dul, Syed R. Husain, Bharat H. Joshi, Christoph Pedain, Raj K. Puri

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

OBJECT: 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. METHODS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
JournalNeurosurgical focus [electronic resource].
Volume20
Issue number4
StatePublished - Aug 21 2006
Externally publishedYes

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Convection
Safety
Catheters
Cytotoxins
Glioma
Central Nervous System Agents
Exotoxins
Interleukin-13
IL13-PE38QQR
Pharmaceutical Preparations
Pseudomonas aeruginosa
Outcome Assessment (Health Care)
Clinical Trials
Bacteria
Pressure
Brain
Therapeutics

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Kunwar, S., Chang, S. M., Prados, M. D., Berger, M. S., Sampson, J. H., Croteau, D., ... Puri, R. K. (2006). Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurgical focus [electronic resource]., 20(4).

Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. / Kunwar, Sandeep; Chang, Susan M.; Prados, Michael D.; Berger, Mitchel S.; Sampson, John H.; Croteau, David; Sherman, Jeffrey; Grahn, Amy Y.; Shu, Vince S.; Dul, Jeanne L.; Husain, Syed R.; Joshi, Bharat H.; Pedain, Christoph; Puri, Raj K.

In: Neurosurgical focus [electronic resource]., Vol. 20, No. 4, 21.08.2006.

Research output: Contribution to journalArticle

Kunwar, S, Chang, SM, Prados, MD, Berger, MS, Sampson, JH, Croteau, D, Sherman, J, Grahn, AY, Shu, VS, Dul, JL, Husain, SR, Joshi, BH, Pedain, C & Puri, RK 2006, 'Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.', Neurosurgical focus [electronic resource]., vol. 20, no. 4.
Kunwar, Sandeep ; Chang, Susan M. ; Prados, Michael D. ; Berger, Mitchel S. ; Sampson, John H. ; Croteau, David ; Sherman, Jeffrey ; Grahn, Amy Y. ; Shu, Vince S. ; Dul, Jeanne L. ; Husain, Syed R. ; Joshi, Bharat H. ; Pedain, Christoph ; Puri, Raj K. / Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. In: Neurosurgical focus [electronic resource]. 2006 ; Vol. 20, No. 4.
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AU - Chang, Susan M.

AU - Prados, Michael D.

AU - Berger, Mitchel S.

AU - Sampson, John H.

AU - Croteau, David

AU - Sherman, Jeffrey

AU - Grahn, Amy Y.

AU - Shu, Vince S.

AU - Dul, Jeanne L.

AU - Husain, Syed R.

AU - Joshi, Bharat H.

AU - Pedain, Christoph

AU - Puri, Raj K.

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N2 - OBJECT: 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. METHODS: 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. CONCLUSIONS: 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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