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Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors


Posted on: 04/20/2008

Link:http://neuro-oncology.dukejournals.org/cgi/content/abstract/15228517-2008-012v1?papetoc

First published on April 10, 2008
Neuro Oncol 2008, DOI:10.1215/15228517-2008-012
© Copyright 2008 by the Society for Neuro-Oncology

Received May 30, 2007
Accepted September 19, 2007

Clinical Investigations

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

John H. Sampson 1*, Gamal Akabani 2, Gerald E. Archer 3, Mitchel S. Berger 4, R. Edward Coleman 2, Allan H. Friedman 3, Henry S. Friedman 3, Kim Greer 2, James E. Herndon II 5, Sandeep Kunwar 4, Roger E. McLendon 6, Alison Paolino 7, Neil A. Petry 2, James M. Provenzale 2, David A. Reardon 3, Terence Z. Wong 2, Michael R. Zalutsky 2, Ira Pastan 8, Darell D. Bigner 6

1 Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Duke University Medical Center, Durham, NC, USA
2 epartment of Radiology, Duke University Medical Center, Durham, NC, USA
3 Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC, USA
4 Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA
5 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA
6 Department of Pathology, Duke University Medical Center, Durham, NC, USA
7 Department of Neurological Surgery, Emory University, Atlanta, GA, USA
8 Laboratory of Molecular Biology, National Cancer Institute, Bethesda, MD, USA

 

* To whom correspondence should be addressed. E-mail: john.sampson@duke.edu .


   Abstract

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of 123I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused 123I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of 123I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses =100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Key Words: brain neoplasms, convection, drug delivery systems, epidermal growth factor receptor, immunotoxins


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