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Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group

Sandeep Kunwar, Michael D. Prados, Susan M. Chang, Mitchel S. Berger, Frederick F. Lang, Joseph M. Piepmeier, John H. Sampson, Zvi Ram, Philip H. Gutin, Robert D. Gibbons, Kenneth D. Aldape, David J. Croteau, Jeffrey W. Sherman, Raj K. Puri

From the University of California San Francisco, San Francisco, CA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Yale University; New Haven, CT; Duke University, Durham, NC; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Illinois at Chicago, Chicago; NeoPharm Inc, Waukegan, IL; US Food and Drug Administration, Center for Biologics Evaluation and Research, Bethesda, MD; and Tel Aviv University, Tel Aviv, Israel

Address reprint requests to Sandeep Kunwar, MD, Department of Neurological Surgery, University of California San Francisco, 400 Parnassus Ave, A808, San Francisco, CA, 94143-0350; e-mail: KunwarS{at}neurosurg.ucsf.edu

Purpose: Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG).

Patients and Methods: Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion.

Results: A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 µg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years.

Conclusion: CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.

Supported in part by Grants No. NIH/NCRR K23 RR16065, NIH/NCI R01 CA097611, 2P50-NS20023, Accelerate Brain Cancer Cure (ABC2), and National Cancer Institute Specialized Programs of Research Excellence in Brain Tumors Grant No. 2P50-NS20023. Cintredekin besudotox (IL13-PE38QQR) is being developed through a cooperative research and development agreement between NeoPharm and the laboratory of Raj K. Puri, MD, PhD, at the US Food and Drug Administration, Center for Biologics Evaluation and Research (Bethesda, MD). The views presented in this article do not necessarily reflect those of the US Food and Drug Administration. The clinical studies were sponsored by NeoPharm Inc.

A list of the other participating investigators and institutions, as well as information regarding partial publication and presentation of data, is included in the Appendix (online only).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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