Treatment > Toxin Therapy

Meeting Abstract

Pre-operative infusion of IL13-PE38QQR cytotoxin by convection-enhanced delivery (CED) in recurrent malignant glioma: A phase I/II study

Z. Ram, G. Barnett, M. Vogelbaum, S. Constantini, K. Lillehei, J. Sherman, C. Fleming, M. Westphal, M. Mehdorn, R. Puri

The Chaim Sheba Medical Center, Tel Hashomer, Israel; Cleveland Clinic Foundation, Cleveland, OH; Tel-Aviv Medical Center, Tel-Aviv, Israel; University of Colorado, Denver, CO; NeoPharm, Inc., Lake Forest, IL; University Hospital Eppendorf, Hamburg, Germany; University Hospital Kiel, Kiel, Germany; United States Food and Drug Administration, Bethesda, MD

IL13-PE38QQR, a recombinant tumor-targeted cytotoxin, combines human IL13 with the enzymatically-active portions of Pseudomonas Exotoxin A (PE_A).
IL13-PE38QQR is highly selective for binding to IL13 receptors (IL13R) on malignant glioma cells, allowing for receptor-mediated endocytosis of PE_A, inhibition of protein synthesis, and tumor cell death.
Malignant gliomas overexpress IL13R, but normal brain tissue expresses little or no IL13R.
Convection-enhanced delivery (CED) using positive pressure infusion is a new approach to delivering therapeutic agents into tumors, or adjacent to tumor resection sites, to optimize drug distribution while minimizing systemic exposure.
The primary objective of Phase I of this study is to determine the maximum tolerated dose (MTD) in terms of duration of infusion and drug concentration of IL13-PE38QQR delivered by continuous infusion (CED) via 1 or 2 intratumoral catheters into recurrent or progressive malignant glioma.
The Phase II objective is determination of the proportion of patients surviving at 6 months.
In Phase I, cohorts of 3-6 patients receive a fixed concentration (0.50 μg/mL) with escalating duration (4-7 days) to determine a MTD based on duration.
After determination of maximum duration, drug concentration is escalated from 1.0-4.0 μg/mL in cohorts of 3-6 patients to determine a MTD based on concentration.
Tumor necrosis is assessed 6-13 days after end of infusion.
As of December 2002, 3 patients have been treated with a 4-day infusion and 4 have received a 5-day infusion.
One patient had to be replaced in the second cohort due to a complication of catheter placement.
Drug-related adverse events include agitation, headache, hypotension, nausea, seizure, and vomiting.
Serious adverse events include brain abscess, intratumoral hemorrhage, and surgical wound infection.
No dose limiting toxicities have been observed.
To date, 2 patients have had disease progression and no deaths have been reported.
Patient accrual to determine the MTD based on duration continues.
The safety and tolerability of IL13-PE38QQR observed in this study have permitted dose escalation.

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