title: Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Neurosurgery, University of California, San Francisco, California 94143-0350, USA. KunwarS@neurosurg.ucsf.edu
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kunwar
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: David
authors.initials: D
authors.lastname: Croteau
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Sherman
authors.forename: Amy Y
authors.initials: AY
authors.lastname: Grahn
authors.forename: Vince S
authors.initials: VS
authors.lastname: Shu
authors.forename: Jeanne L
authors.initials: JL
authors.lastname: Dul
authors.forename: Syed R
authors.initials: SR
authors.lastname: Husain
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.forename: Christoph
authors.initials: C
authors.lastname: Pedain
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001932:Brain Neoplasms / Q000188:drug therapy*; D002408:Catheters, Indwelling / Q000009:adverse effects / Q000592:standards; D016503:Drug Delivery Systems / Q000009:adverse effects / Q000379:methods* / Q000639:trends; D004358:Drug Therapy / Q000379:methods* / Q000639:trends; D005098:Exotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D007260:Infusion Pumps / Q000009:adverse effects / Q000639:trends*; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D005098:Exotoxins; C521502:IL13-PE38; D000922:Immunotoxins; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins