Safety, Tolerability, and Tumor Response of IL4-Pseudomonas Exotoxin (NBI-3001) in Patients with Recurrent Malignant Glioma |
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Authors: | Friedrich Weber Anthony Asher Richard Bucholz Mitchel Berger Michael Prados Susan Chang Jeffrey Bruce Walter Hall Nikolai G Rainov Manfred Westphal Ronald E Warnick Robert W Rand Frank Floeth Frank Rommel Henry Pan Vijay N Hingorani Raj K Puri |
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Institution: | (1) Department of Neurological Surgery, Heinrich Heine University, Düsseldorf, Germany;(2) Carolina Neurosurgery and Spine Associates, Charlotte, NC;(3) St. Louis University School of Medicine, St. Louis, MO;(4) Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA;(5) Columbia University, New York, NY;(6) University of Minnesota, Minneapolis, MN, USA;(7) Klinik für Neurochirurgie, Martin-Luther Universität Halle-Wittenberg, Halle;(8) Neurochirurgische Klinik, Universität Krankenhaus Eppendorf, Hamburg, Germany;(9) University of Cincinnati, Cincinnati, OH;(10) John Wayne Cancer Institute, Santa Monica, CA;(11) Neurocrine Biosciences, Inc., San Diego, CA;(12) the Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, United States Food and Drug Administration, NIH, Bethesda, MD, USA |
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Abstract: | Purpose: This was an open-label, dose-escalation trial of intratumoral administration of IL-4 Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma.
Patients and methods: A total of 31 patients with histologically verified supratentorial grades 3 and 4 astrocytoma were studied. Of these, 25 patients were diagnosed with glioblastoma multiforme (GBM) while six were diagnosed with anaplastic astrocytoma. Patients were over 18 years of age and had Karnofsky performance scores 60. Patients were assigned to one of four dose groups in a dose-escalation fashion: 6µg/ml×40ml,9µg/ml×40ml,15µg/ml×40ml, or 9µug/ml×100ml of NBI-3001 administered via convection-enhanced delivery intratumorally using stereotactically placed catheters. Patients were followed with serial MRI scans and clinical assessments every four weeks for the first 16 weeks and then every eight weeks until week 26.
Results: No drug-related systemic toxicity, as evident by lack of hematological or serum chemical changes, was apparent in any patients; treatment-related adverse effects were limited to the central nervous system. No deaths were attributable to treatment. Drug-related grade 3 or 4 toxicity was seen in 39% of patients in all dose groups and 22% of patients at the maximum tolerated dose of 6µug/ml×40ml. The overall median survival was 8.2 months with a median survival of 5.8 months for the GBM patients. Six-month survival was 52% and 48%, respectively. Gadolinium-enhanced magnetic resonance imaging of the brain showed areas of decreased signal intensity within the tumor consistent with tumor necrosis following treatment in many patients.
Conclusions: NBI-3001 appears to have an acceptable safety and toxicity profile when administered intratumorally in patients with recurrent malignant glioma. |
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Keywords: | astrocytoma glioblastoma multiforme immunotoxin intratumoral therapy malignant glioma |
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